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ReviewMarch 10, 2020

Multitarget Approaches against Multiresistant Superbugs
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Declan Alan Gray
Declan Alan Gray
Newcastle University Biosciences Institute, Newcastle University, NE2 4HH Newcastle upon Tyne, United Kingdom
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Michaela Wenzel*
Michaela Wenzel
Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden
*Email: [email protected]. Tel: 0046-31-772-2074.
More by Michaela Wenzel
http://orcid.org/0000-0001-9969-6113

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ACS Infectious Diseases

Cite this: ACS Infect. Dis. 2020, 6, 6, 1346–1365

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https://doi.org/10.1021/acsinfecdis.0c00001

Published March 10, 2020

Abstract

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Despite efforts to develop new antibiotics, antibacterial resistance still develops too fast for drug discovery to keep pace. Often, resistance against a new drug develops even before it reaches the market. This continued resistance crisis has demonstrated that resistance to antibiotics with single protein targets develops too rapidly to be sustainable. Most successful long-established antibiotics target more than one molecule or possess targets, which are encoded by multiple genes. This realization has motivated a change in antibiotic development toward drug candidates with multiple targets. Some mechanisms of action presuppose multiple targets or at least multiple effects, such as targeting the cytoplasmic membrane or the carrier molecule bactoprenol phosphate and are therefore particularly promising. Moreover, combination therapy approaches are being developed to break antibiotic resistance or to sensitize bacteria to antibiotic action. In this Review, we provide an overview of antibacterial multitarget approaches and the mechanisms behind them.

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SPECIAL ISSUE

This article is part of the Antibiotics special issue.

Antimicrobial resistance has developed into a global healthcare crisis that has culminated in the emergence of multidrug-resistant bacteria that are no longer treatable with any common antibiotic. (1) For example, recently emerging Neisseria gonorrhoeae strains resistant to third-generation carbapenems led to a number of untreatable gonorrhea infections in the UK. (2) Despite considerable investments, the development of innovative, resistance-breaking antibiotics still progresses too slowly. (3,4) For a long time, antibiotics with one specific protein target were highly sought after in drug design and screening efforts. Single target drugs were propagated as the ideal antibiotics with the argument that a high target specificity equals less side effects. This resulted in a predominantly genomic-driven approach to antibiotic discovery, where single protein targets were evaluated, while compounds with multiple or complex targets were regarded to be unspecific and unsuitable for further development. However, the last decades have shown that resistance to antibiotics with specific single protein targets develops too fast to be sustainable, and the realization emerged that candidates with multiple targets are worth pursuing for their slower resistance development rates. (5−7) In fact, long-established antibiotic drugs with great clinical success rarely target only one specific molecule. For example, β-lactam antibiotics typically target more than one transpeptidase, and quinolones inhibit both topoisomerases II and IV. (8,9) Antibiotics that truly have one single protein target, such as sulfonamides targeting an enzyme involved in folate synthesis or rifampicin targeting RNA polymerase, are famous for high resistance development and are therefore usually administered in combination regimes. (10,11)

Naturally occurring antibiotics often do not have strict single targets either. The most common class of natural antimicrobial substances are antimicrobial peptides, which occur in virtually all organisms. These molecules predominantly target complex bacterial structures, e.g., the cell membrane, the cell wall, or both. (12,13) Moreover, antibiotic producers often produce a mix of structurally related compounds. This is, for example, the case for gramicidin (contain gramicidin A–C), tyrothricin (contains gramicidin A–C and tyrocidine A–D), and polymyxins (contains multiple peptides with small structural variations depending on the polymyxin type). (14,15) Such small structural variations can result in slightly different target interactions (16−20) and may complicate resistance development by target alterations and antibiotic-cleaving or scavenging molecules. Naturally occurring mixes have been used in clinical settings with great success and in some cases are combined with each other or other antibiotics like neomycin. (21,22) It is quite common in clinical practice to use antibiotic combinations for different reasons. For example, trimethoprim is combined with sulfonamides to prevent quick resistance development by a single target mutation, and erythromycin is often given together with penicillin for their synergistic effect. (23) Since more and more pathogens become resistant to individual antibiotics, it has become pivotal to thoroughly explore multitarget approaches to combat resistant bacteria. In this Review, we provide an overview of multitarget antibiotics and combination approaches that are in current clinical use or have a chance to be applied in clinical settings in the future.

Part 1: Multitarget Compounds

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Generally, the ability of a single drug to interact with more than one specific target is called polypharmacology. (24) When talking about multitarget antibiotics, we distinguish between different levels of multitargeting. In this Review, we use the terminology intrinsically multi-effective, multitarget, and multifunctional. Intrinsically multi-effective compounds may have a single target, but this molecule or structure is involved in multiple processes, which are all affected by its inhibition. Multitarget antibiotics can be divided into multitarget compounds that target more than one isoenzyme or closely related proteins of the same pathway and multitarget compounds that bind to different molecules involved in separate cellular processes. Multifunctional compounds have a direct antibiotic target but an additional indirect antibacterial activity, e.g., immunomodulatory properties. Table 1 gives an overview of prominent antibiotics of these categories that are used in the clinic.

Table 1. Examples for Clinically Used Antibiotics with Multiple Mechanisms of Action

antibiotic	targets	mechanism of action	ref
Intrinsically Multi-effective
daptomycin	phosphatidylglycerol, fluid lipid domains	binds to phosphatidylglycerol, inserts into fluid lipid domains that harbor the cell wall synthesis machinery, immediately inhibits cell wall and membrane synthesis; prolonged treatment results in partial membrane depolarization and impairs several other membrane-bound processes	(25,26)
gramicidin S	membrane	induces membrane phase separation causing inhibition of cell envelope synthesis and cell division	(20)
vancomycin	lipid II	binds to lipid II, thereby inhibits peptidoglycan synthesis and depletes the pool of bactoprenol phosphate, additionally resulting in the inhibition of wall teichoic acid synthesis	(27,28)
bacitracin	bactoprenol pyrophosphate	depletes the pool of bactoprenol phosphate resulting in inhibition of peptidoglycan and wall teichoic acid synthesis	(29)
nitrofurantoin	cellular macromolecules	generates reactive oxygen species, which damage cellular macromolecules including DNA and membrane lipids	(30,31)
acyldepsipeptides	Clp protease	deregulates the Clp protease resulting in unspecific degradation of a variety of proteins	(32,33)
bedaquiline	ATP synthase	inhibits ATP synthase, depleting the ATP pool and resulting in the inhibition of all energy-consuming cellular processes	(34)
Multitarget
penicillin	penicillin-binding proteins	inhibits multiple penicillin-binding proteins	(8)
ciprofloxacin	topoisomerase II and IV	inhibits topoisomerase II and IV	(9)
tetracycline	ribosome and membrane	blocks attachment of loaded aminoacyl tRNA to the A-site of the ribosome; also impairs membrane function	(31,35)
polymyxin B	outer and inner membrane	permeabilizes both the outer and inner membrane of Gram-negative bacteria	(36)
tyrocidine	membrane and probably DNA	forms defined ion-conducting membrane pores; probably additionally binds to DNA	(20,37,38)
Multifunctional
clindamycin	50S rRNA	anti-inflammatory	(39,40)
clofazimine	guanine	anti-inflammatory	(41−43)
dapsone	dihydropteroate synthase	anti-inflammatory and immunomodulatory	(44,45)
macrolides	50S rRNA	anti-inflammatory and immunomodulatory	(46−48)
metronidazole	DNA	anti-inflammatory	(49,50)
rifampicin	DNA-dependent RNA polymerase	anti-inflammatory and immunomodulatory	(51,52)
tetracycline	ribosome and membrane	anti-inflammatory	(53−55)

Intrinsically Multi-effective

The most common antimicrobial target, whose inhibition results in a multitude of cellular effects, is the cytoplasmic membrane. It is the target of many natural antibiotics, most prominently host defense peptides. (12) The cytoplasmic membrane harbors essential cellular processes, such as the respiratory chain and cell wall synthesis (Figure 1A), and many more important components, including nutrient uptake, secretion, and stress response systems. Thus, membrane-targeting antibiotics have the potential to (i) inhibit processes essential for survival, (ii) reduce bacterial fitness, (iii) impair virulence, and (iv) interfere with stress adaptation. Depending on how an antibiotic interferes with the membrane, few or a whole array of membrane-bound processes can be affected. (20) Several membrane-active antibiotics are used in the clinic, although only a handful are applied systemically. For some of them, their multiple effects on bacterial cells have been studied.

Many membrane-active antibiotics dissipate the membrane potential. This depolarization has a number of downstream effects due to the depletion of ATP and the subsequent impairment of ATP-dependent processes. Moreover, it leads to the displacement of peripheral membrane proteins that bind to the membrane surface by electrostatic interactions, such as the cell division proteins FtsA and MinD. (56,57) However, not all membrane effects can be explained by membrane depolarization. Thus, the membrane pore-forming peptides tyrocidine A and C not only dissipate the membrane potential and lead to leakage of ions and small molecules but also reduce membrane fluidity, diminish membrane domains, and affect the localization of several membrane-bound processes, including cell division, peptidoglycan synthesis, phospholipid synthesis, respiration, and ATP synthesis. (20) Such effects are not observed when the membrane potential is dissipated by specific ionophores. (56,57) The structurally similar peptide gramicidin S, which does not form distinct membrane pores and has milder effects on membrane potential and fluidity, only affects cell division and cell envelope synthesis proteins. (20,58) Daptomycin, which is one of the few systemically applied membrane-targeting antibiotics, has recently been described to interfere with both peptidoglycan and phospholipid synthesis by interfering with fluid membrane microdomains that harbor the lateral cell wall synthesis machinery. (25,31,59)

Similar results have been obtained for host defense peptides and experimental compounds that are not yet in clinical application. For example, human β-defensin 3 forms a dimeric raft-like structure with two α-helices anchoring it to the hydrocarbon layer and binds to negatively charged lipid head goups. (60) It has also been shown to bind the cell wall precursor lipid II with low affinity, probably due to electrostatic interactions with the pyrophosphate group. (61) Thus, the defensin is attracted to sites of active cell division and cell wall synthesis, where its presence disturbs the interactions of the complex peptidoglycan synthetic machinery, which was coined the “sand in the gearbox” effect. (61) The structurally similar human β-defensin 2 binds to distinct membrane foci at nascent cell division septa, where it disturbs the function of SecA and sortase A, which specifically localize to these sites and are involved in the secretion of virulence factors. (62) Other membrane-active compounds have been observed to have broader effects. For example, the membrane-disruptive peptides TC19 and TC84, which are derived from the microbicidal blood platelet protein thrombocidin, (63) lead to large-scale disruption of membrane organization and affect a multitude of cellular processes, including cell division, peptidoglycan synthesis, phospholipid synthesis, respiration, ATP synthesis, and spore outgrowth. (64−66) Such a broad panel of effects raises the following questions: which ones are due to the multifaceted mechanisms of the compounds and which are merely a consequence of cell death? It is therefore pivotal to examine the mechanism of a compound after short treatment times with sublethal concentrations. (4) The comparison of the effects observed under these conditions with those occurring at lethal concentrations or after prolonged treatment can give insight into which effects lead to cell death and which are a consequence thereof. In the case of the TC19 and TC84 peptides, membrane depolarization, rigidification, and phase separation were already observed at sublethal concentrations and increased at lethal concentrations, while other observations like protein delocalization and intracellular content leakage were mainly observed at lethal concentrations or after prolonged treatment. (64,65) This suggests that the primary mechanism of these peptides is the disruption of membrane organization. Similarly, depolarization and limited ion leakage are observed with daptomycin at high concentrations and long treatment times. However, at inhibitory, and even lethal, concentrations these effects do not occur, suggesting that increased membrane permeability is a consequence of cell death and not the primary mechanism by which it occurs. (67)

However, broad effects do not necessarily need to be a mere consequence of membrane disruption. Similar effects have been achieved by other compounds with quite creative molecular mechanisms. For example, the cyclic hexapeptide cWFW induces large-scale phase separation sorting peripheral and integral membrane proteins into two distinct domains, (68) and the plant-derived antibiotic candidate rhodomyrtone forms large membrane vesicles that irreversibly trap both peripheral and transmembrane proteins. (69)

Another molecular target that intrinsically presupposes multiple effects is the peptidoglycan precursor lipid II, which is the antibiotic target of the glycopeptide antibiotics vancomycin, telavancin, oritavancin, dalbavancin, and teicoplanin. (70−73) Lipid II is also the target of a variety of lantibiotics, most prominently the food preservative nisin. While nisin and other type A lantibiotics, such as gallidermin and epidermin, additionally target the cell membrane, (13,74,75) type B lantibiotics like mersacidin do not seem to have additional membrane effects. (74,76) Though the application of lantibiotics for antimicrobial coatings, e.g., for implants, is being explored, (77) none of them is currently used in a clinical setting. Lipid II is synthesized in the cytosol and attached to a lipid carrier molecule, undecaprenol phosphate, yielding the peptidoglycan building block lipid II. Lipid II flips over the membrane to the cell surface, and when the building block is incorporated into the cell wall, undecaprenyl phosphate flips back over the membrane to the cytosolic side, where it can undergo another cycle of peptidoglycan synthesis. (78) However, undecaprenyl phosphate is also used in the biosynthesis of wall teichoic acids, an important component of the Gram-positive bacterial cell wall. (78,79) The binding of antibiotics to lipid II not only directly prevents the incorporation of peptidoglycan building blocks into the cell wall but also depletes the undecaprenyl phosphate pool and thus concomitantly impairs the wall teichoic acid synthesis. Likewise, compounds that bind undecaprenyl phosphate (e.g., friulimicin B) or undecaprenol pyrophosphate (bacitracin) simultaneously inhibit both processes (Figure 1B). Moreover, cell wall synthesis is coupled to other cellular processes, most prominently cell division, and the binding of antibiotics to the sites of cell wall synthesis is likely to have additional “sand in the gearbox” effects. (61) Due to their typically large size and/or hydrophobic or amphipathic properties, membrane and cell wall-targeting antibiotics rarely cross the outer membrane of Gram-negative bacteria and are mostly used against and studied in Gram-positives. However, the general principle of the intrinsically multiple effects of such compounds is the same in all organisms.

These effects have also been predicted for other multiprotein machineries like the respiratory chain. Indeed, the inhibition of respiration and/or ATP synthase and subsequent depletion of ATP pools have been observed for several compounds, whose primary target is the cell membrane. (58,69,80−82) Membrane potential and respiration are closely intertwined, and the impairment of one can lead to the inhibition of the other. (83,84) Either way, both will have downstream effects on the performance of ATP synthase and the availability of ATP for important cellular processes (Figure 1C). Currently, no respiratory chain inhibitor is available as an antibiotic on the market, but with bedaquiline, the first ATP synthase inhibitor was marketed for the treatment of tuberculosis in 2012. (34) The impairment of the electron transport chain can also generate reactive oxygen species and thus cause oxidative stress. (85) This leads to widespread oxidative damage to cellular macromolecules, including DNA, proteins, and the cell membrane. (86) Oxidative damage is also a key mechanism of killing pathogenic bacteria by the immune system that is mediated by neutrophils. (87) While the generation of reactive oxygen species may be a side effect of membrane-targeting antibiotics, there is one antibiotic in the clinic that makes targeted use of oxidative stress. Nitrofurantoin, which is used against urinary tract infections, is a pro-drug that is activated by cellular nitrofuran reductases resulting in reactive intermediates that damage cellular macromolecules, especially DNA. (30,31)

Another mechanism that should be mentioned in this category is the deregulation of the ClpP protease by acyldepsipeptide antibiotics. ClpP takes part in both the general degradation of misfolded proteins and the regulated proteolysis of a range of substrates, including transcription factors and regulatory proteins. Acyldepsipeptides deactivate the tight control mechanisms that normally ensure that only such proteins that are either defective or supposed to be degraded as part of a regulatory cascade are degraded by ClpP. This leads to the uncontrolled proteolysis of intact cytosolic proteins and among them the key cell division protein FtsZ. (32,33,88)

Translation inhibitors that target the bacterial ribosome always bind to rRNAs, which are encoded in multiple copies in the bacterial genome. (5,89) While they only have one binding site, their resistance development rates are reduced, since simple point mutations are unlikely to affect all gene copies. (5) Translation inhibitors are also intrinsically multi-effective antibiotics, since an impaired ability to produce proteins hampers multiple cellular processes including the ability to elicit an appropriate stress response and thus prevents stress adaptation. Next to β-lactams, ribosome inhibitors constitute the most successful antibiotic class in the clinic, underlining the potential of compounds with multiple targets.

Multiple Targets in the Same Pathway

Most of the antibiotics described above target one specific cellular structure, which itself is involved in different processes. However, there are also several antibiotics that bind to two or more distinct molecules. We will first discuss those compounds that target related proteins of the same pathway. The most extreme examples for this are the β-lactam antibiotics, which typically target more than one penicillin-binding protein (PBP) (Figure 1D). (8) For example, Escherichia coli has 8 PBPs, 6 of which are inhibited by penicillin G. (90−92) Other examples include quinolone antibiotics, which target both topoisomerase II and IV involved in DNA supercoiling and resolving DNA concatemers, respectively, (9) and the cell wall synthesis inhibitors fosfomycin and d-cycloserine. Gram-positive bacteria possess two copies of MurA, the first enzyme in the lipid II synthesis pathway, and fosfomycin inhibits both isoenzymes. (93)d-Cycloserine competitively inhibits both alanine racemase and d-ala-d-ala ligase, which converts l-alanine to the d-alanine dipeptide that is part of the peptidoglycan interpeptide bridge. (94) Similarly, platencin, a fatty acid synthesis inhibitor that attracted significant attention upon its discovery but then encountered several hurdles in preclinical development, (95) is a dual inhibitor of the FabF and FabH enzymes. (96,97)

Multiple Targets in Different Pathways

Several antibiotics have been found that inhibit two or more distinct targets that are not closely related components of the same pathway or process. Not only is it more difficult to acquire target-based resistance in two different molecules, but also bacteria need to react with two different stress responses to mitigate antibiotic action, hampering their capabilities for efficient stress adaptation; thus, these antibiotics have an additional advantage.

There are several examples for such compounds in the clinic, and new molecules with multiple targets are regularly discovered. One example are the polymyxins, in particular polymyxin B and colistin, which are used as last resort antibiotics against multiresistant Gram-negative infections. (98) These polypeptides target both the outer and the inner membrane of Gram-negative bacteria (99,100) (Figure 1E). Another example is clofazimine, which is used to treat leprosy. (101) This antibiotic binds to guanine bases in bacterial DNA but also increases phospholipase A1 activity, leading to toxic overproduction of lysophospholipids. (102) The atypical tetracycline chelocardin, which has recently attracted renewed interest for clinical development, (103,104) inhibits the bacterial ribosome and additionally depolarizes the cytoplasmic membrane. (105) Tetracycline itself, while not leading to depolarization, has recently been shown to disturb membrane organization in addition to translation inhibition. (31) The same was observed for anhydrotetracycline, suggesting that this dual activity could be a general activity of the tetracycline class. (31) It would be reasonable to assume that membrane activity may be a general consequence of translation inhibition, since ribosomes associate with the cell membrane to couple translation to protein secretion. (106) However, other ribosome inhibitors did not visibly disturb the cell membrane, and a ribosomal protein mutant that diminishes tetracycline binding to the ribosome showed the same tetracycline-induced membrane effects as the wild-type. (31) These findings suggest that the membrane activity of tetracycline is independent from translation inhibition and thus a separate secondary target. Similarly, tyrocidines, which primarily disrupt cytoplasmic membrane integrity, have long ago been proposed to bind DNA as secondary target. This notion, which was derived from test tube interactions of the peptides with isolated DNA, (38) was only recently supported by in vivo experiments. (20)

Another very prominent example are antibiotics with a dual mechanism on cell wall synthesis and the cell membrane. This is relatively common, since cell wall synthesis inhibitors often target membrane-bound steps of this pathway. Thus, both targets are in close proximity. The most prominent example for this is the lantibiotic nisin, which is not used clinically but is a common food preservative (Figure 1F). Nisin has a two-step mechanism of action. It first establishes contact with lipid II, inhibiting peptidoglycan synthesis. It then inserts into the lipid bilayer to form a transmembrane pore. (107−109) More recently, it was found that nisin also binds to undecaprenyl phosphate, adding another structure to its list of molecular targets. (110) While nisin is able to bind to negatively charged lipids in the absence of lipid II or undecaprenyl phosphate, (111) it needs the lipid-coupled cell wall precursor as a docking molecule to form a transmembrane pore. Other lantibiotics like gallidermin can impair both targets independently. (112) This property of lantibiotics also inspired the development of dual-function vancomycin derivatives. Telavancin and oritavancin carry a hydrocarbon tail, which allows them to insert into the cell membrane after binding lipid II. Thereby, they disrupt the permeability barrier, a feature that vancomycin is lacking and that restores activity against strains with high-level vancomycin resistance. (7,71) Daptomycin could be included in this group as well, since it likewise inserts into the cell membrane and impairs cell wall synthesis. (25) However, at least to our current knowledge, it only binds a single molecular target, namely, phosphatidylglycerol-containing lipids. (113−116)

Designer Dual-Target Compounds

Inspired by the clinical success of these multitarget antibiotics, approaches have been undertaken to develop dual-target molecules. These can either be stable hybrids combining two functions in one molecule or cleavable compounds, whereby the prodrug has a different target than the cleavage product. (117,118) In the past, cleavable compounds have essentially behaved like simple prodrugs for the cleavage product rather than eliciting their intended dual effects. Hence, newer efforts rather focus on stable hybrids. (118−120) These approaches have been recently reviewed in detail, (117,121) but we want to give a brief overview of the molecules that are currently underway in clinical development (Table 2).

Table 2. Antibiotic Hybrid Molecules Currently under Clinical Development

compound	antibiotic 1 inhibited process 1	antibiotic 2 inhibited process 2	stage	ref
cadazolid	quinolone topoisomerases II and IV	oxazolidinone translation	phase III	(122)
cefilavancin (TD-1792)	vancomycin lipid II	cephalosporin PBPs	phase III	(123)
DNV3837 (MCB-3681)^a	fluoroquinolone topoisomerases II and IV	oxazolidinone translation	phase II	(124)
TNP-2092 (CBR-2092)	rifamycin RNA polymerase	quinolone topoisomerases II and IV	phase II	(120)
TD-1607	glycopeptide lipid II	cephalosporin PBPs	phase I	(125)

^{^a}

MCB-3681 was developed into the prodrug MBB-3837, which was renamed DNV3837 after Morphochem was acquired by Deinove.

Cadazolid is a stable hybrid of a quinolone and oxazolidinone and currently in phase III clinical trials for the treatment of Clostridium difficile infections. (122,126) It primarily inhibits translation but also topoisomerase activity and shows low resistance development rates. (127) Cefilavancin is a stable hybrid molecule of vancomycin and a third-generation cephalosporin, which is currently undergoing phase III clinical trials for complicated skin and soft tissue infections. (121) This hybrid compound is active against both methicillin and vancomycin-resistant Staphylococcus aureus, yet it has not been verified to which extent it inhibits lipid II and PBPs. (128,129) MCB-3681 is a stable fluoroquinolone–oxazolidinone hybrid similar to cadazolid. (124) It is active against strains that are resistant to both ciprofloxacin and linezolid. (130) MCB-3681 was scheduled to undergo phase II clinical trials since 2015 and was granted fast track status by the FDA in 2016. (124) Instead, it was further developed into a prodrug molecule, MCB-3837. In 2018, its developing company Morphochem was acquired by Deinove, and the compound, now under the name DNV3837, finally went into phase II clinical trials for treatment of C. difficile infections in 2019. (131) The study is planned to be completed in the summer of 2020. (132) TNP-2092 is a stable rifamycin–quinolone hybrid currently in phase II trials for prosthetic joint infections. (120) It is active against a range of quinolone and rifamycin-resistant strains. (120) TNP-2092 is also being evaluated against Helicobacter pylori infections yet at a preclinical stage. (133) TD-1607 is a stable glycopeptide–cephalosporin hybrid similar to cefilavancin. Two phase I clinical trials have been completed, yet results remain to be published. (121,125)

A different hybrid approach was followed by the company Visterra, who developed an ultranarrow spectrum hybrid molecule against P. aeruginosa infections by coupling a specific antibody that targets cell surface glycan molecules with an antimicrobial peptide. (134) Here, the hybrid molecule does not possess two antibacterial targets, but the antibody strategy allows more targeted treatment by increasing the local peptide concentration at the cell surface and bringing the antibiotic group close to its target.

Another approach to new multifunctional antibiotic candidates against Gram-negative bacteria based on the polymyxin lead structure has recently been published. (135) These compounds are chimeric peptidomimetics combining features of polymyxin A with the outer membrane protein-targeting cyclic peptide murepavadin. They permeabilize the outer membrane by targeting lipopolysaccharides, inhibit the outer membrane protein complex Bam, which is involved in the folding and insertion of β-barrel proteins in the outer membrane, and permeabilize the inner membrane. (135) One of these compounds is currently undergoing preclinical toxicology studies. (135)

It will be exciting to see whether these hybrid molecules will receive FDA approval and how they will ultimately perform in the clinic.

Multifunctional Compounds

The last category of multitarget molecules that we want to discuss are multifunctional compounds, which in addition to their antibacterial properties possess a second, unrelated activity that is beneficial for treatment. Most prominently, such compounds may have anti-inflammatory or immunomodulatory properties (Table 1). This is well-described for a range of antibiotics, and some are even used to treat conditions unrelated to infections due to these properties. This is, for example, the case for macrolides, which are used to treat diffuse panbronchiolitis, (47) dapsone, which has anti-inflammatory and immunomodulatory effects and is, for example, used against dermatitis herpetiformis, (136) or rifampicin, used against pruritus caused by primary biliary cholangitis. (137) For other indications, the dual effects of these compounds are crucial for their therapeutic efficacy. For example, clindamycin is used to treat acne for both its direct antibacterial action and its ability to decrease swelling and inflammation by modulating cytokine production. (40,138) Acne is a very common indication for combining antibacterial and anti-inflammatory activities. Other antibiotics with this dual function are metronidazole, tetracycline, macrolides, and dapsone, which are all used to treat acne. (48) Clofazimine, which is used against leprosy, already has two distinct antibacterial targets, guanine bases and phospholipase A2. (102) In addition to these activities, it also reduces neutrophil mobility, which is beneficial for treating patients with a type 2 lepra reaction characterized by strong inflammation. (139,140) The range of antibiotics with immunomodulatory and anti-inflammatory effects and the detailed use of these compounds have been thoroughly reviewed before (48,141−143) and should not be described here in more detail. However, it should be noted that daptomycin has been implicated to have immunomodulatory effects as well. (144) Daptomycin already has multiple effects on bacterial cells, and both tetracycline and clofazimine have two distinct antibacterial targets. This illustrates that multiple activities are quite common in clinically successful antibiotics.

Part 2: Antibiotic Combinations

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Combination regimes are nowadays quite common in the clinic, normally to potentiate activity against multiresistant strains and prevent resistance development. A common regime is, for example, the combination of sulfonamides with trimethoprim in urinary tract infections (Figure 2).

Figure 2. Prevention of resistance development by combination therapy. Sulfonamide antibiotics are typically given together with trimethoprim to prevent fast target mutation of a single enzyme.

Table 3 gives an overview of well-characterized antibiotic combinations and their effects. A significant amount of research is being conducted to find combinations that are more effective than monotherapy or that are resistance-breaking. When two antibiotics are combined, they are usually either indifferent in their activity or more effective in killing bacteria due to additive effects. However, if the effects of the combination exceed the expected additive effects, the combination is called synergistic. This is, for example, the case for daptomycin and β-lactams. (145) The opposite effect is called antagonistic and is observed, e.g., with the antifungal drugs amphotericin B and ravuconazole. (146) Synergistic drug combinations are highly sought after, since they allow one to lower drug doses and thus may reduce side effects. A different approach to combination strategies is using potentiators, sometimes also called antibiotic adjuvants. These are compounds that by themselves have little or no antibacterial activity but enhance the effects of antibiotics when administered in combination. This is, for example, the case for resistance-breaking compounds like β-lactamase inhibitors. (147) Such compounds typically target either acquired or intrinsic antibiotic resistance mechanisms. There have also been approaches to develop inhibitors of horizontal gene transfer to prevent the spread of resistance genes. (148) In the following, we will discuss these different approaches to antibiotic combination therapy.

Table 3. Examples for Well-Characterized Antibiotic Combinations^a

antibiotic 1	antibiotic 2	mechanism of combination	ref
synergistic
d-cycloserine inhibits peptidoglycan synthesis	epigallocatechin gallate binds to and disrupts the peptidoglycan layer	d-cycloserine inhibits lipid II synthesis, and epigallocatechin gallate disrupts cell wall peptidoglycan	(149)
ampicillin^b inhibition of PBPs	daptomycin inhibition of membrane and cell wall synthesis	daptomycin affects membrane organization, which might interfere with the function of PBPs; it also inhibits lipid II synthesis by abolishing membrane binding of MurG	(25,150,151)
rifampicin^b RNA synthase inhibition	fusidic acid ribosome inhibition	mechanism unknown, but it has been observed in vitro that DNA-dependent RNA-polymerase is inhibited by the elongation factor T	(152−155)
erythromycin^b ribosome inhibition	penicillin inhibition of PBPs	inhibition of translation might deplete β-lactamases	(153,156,157)
additive
ampicillin^b inhibition of PBPs	imipenem inhibition of PBPs	both antibiotics bind to the same site of PBP2A but with low affinity	(150,158,159)
azithromycin^b ribosome inhibition	imipenem inhibition of PBPs	inhibition of translation might deplete PBPs, requiring lower doses of imipenem	(160,161)
indifferent
sulphamethoxazole^b inhibits dihydropteroate synthetase	trimethoprim inhibits dihydrofolate reductase	both compounds target folate synthesis but at different steps; a combination is given to prevent rapid resistance development to a single drug rather than increase activity	(162−164)
potentiative
amoxicilline^b inhibition of PBPs	clavulanate β-lactamase inhibitor	clavulanate inhibits the β-lactamase that degrades amoxicilline	(165,166)

^{^a}

PBP: penicillin-binding protein.

^{^b}

Combination in clinical use.

Antibiotic Synergy

Synergistic compound combinations are known against Gram-positive and Gram-negative bacteria and mycobacteria. However, the exact mechanisms of antibiotic synergy are mostly unknown. While there have been attempts to explain synergy, these have rarely been experimentally proven. However, there are four widely accepted categories of possible synergistic mechanisms for which examples are known (Figure 3).

Figure 3. Mechanisms of synergy. (A) Targeting the same molecule (here, plectasin in red–yellow and dalbavancin in green–blue), (B) targeting the same pathway (here, plectasin in red–yellow and moenomycin in green–blue), (C) targeting a related process (here, LL-37 in green–blue and teicoplanin in red–yellow), and (D) improving target accessibility (here, colistin in red–yellow and minocycline in green–blue).

One possible synergistic mechanism is the inhibition of the same target molecule at multiple binding sites (Figure 3A). An example for this is the synergy of plectasin with teicoplanin and dalbavancin, which all bind the peptidoglycan precursor lipid II. (167) However, this is not a universal phenomenon, and other antibiotics that target the same molecule might only have additive effects. This is, for example, the case for the PBP inhibitors ampicillin and imipenem. (150) Another possibility for synergy is that two compounds inhibit independent targets in the same pathway (Figure 3B). This is for example the case for d-cycloserine, an antituberculosis drug that inhibits an intracellular step of peptidoglycan synthesis, (168) and epigallocatechin gallate, a compound found in tea that is thought to disrupt cell wall peptidoglycan. (149,169) Epigallocatechin gallate also acts synergistically with β-lactam antibiotics (149) and inhibits β-lactamase activity. (170) Another example for this synergistic mechanism is again plectasin, which also acts synergistically with the glycosyltransferase inhibitor moenomycin. (167) However, plectasin does not show synergy with other cell wall synthesis inhibitors like vancomycin or penicillin G, demonstrating that the exact mechanisms underlying synergy are little understood. (167) Synergy can also be observed between compounds that inhibit related processes (Figure 3C). This can often be observed for antibiotics that target cell wall synthesis and membrane-active compounds, e.g., β-lactams and daptomycin (150,171,172) or the cationic antimicrobial peptide LL-37 and the lipid II-binding antibiotic teicoplanin. (173) In some cases, synergy is also observed between antibiotics with different targets in unrelated pathways as observed with penicillin and the ribosome inhibitor erythromycin. Here, it has been suggested that the depletion of penicillin-binding proteins by translation inhibition might be the underlying mechanism. (157) However, a similar combination of azithromycin (ribosome inhibitor) and imipenem (β-lactam) only results in additive effects. (174) The last documented mechanism underlying antibiotic synergy is the improvement of target accessibility (Figure 3D). This is, for example, observed with the outer membrane-permeabilizing peptide colistin in combination with drugs that have inner membrane-bound or cytosolic targets, such as the β-lactam meropenem, the ribosome inhibitor minocycline, and fosfomycin, which inhibits the first enzyme in the lipid II pathway. (175) This is an important anti-Gram-negative strategy that will be discussed in more detail in the following chapter. Antibiotic synergy has attracted significant attention over the last years, and efforts are being undertaken to discover new synergistic combinations that can be useful for clinical applications. (176−180)

Permeabilizers

In addition to synergistic antibiotic combinations, potentiative combination approaches have recently attracted increased attention. Potentiators typically target intrinsic or acquired antibiotic resistance mechanisms to sensitize or resensitize bacteria to existing antibiotics (Figure 4).

The advantage of these molecules is that they can potentially increase the activity of a whole array of existing antibiotics. One class of potentiators are cell envelope permeabilizers, especially outer membrane-permeabilizing compounds (Figure 4A). These are particularly interesting, since the outer membrane is the main reason why most antibiotics are ineffective against Gram-negative bacteria. The inactivation of this permeability barrier could make almost the whole array of current antibiotic drugs available for treating these infections, instead of the handful that we have at our disposal now. Two antibiotics in current clinical use are known to target the outer membrane of Gram-negative bacteria, colistin and polymyxin B. Both of them display synergy with antibiotics with intracellular targets, which can at least partially be attributed to increased outer membrane permeability. (175,181,182) Many other outer membrane-permeabilizing agents are known, for example, chelators like EDTA, metal ions, and certain antimicrobial peptides, but many of these have little clinical promise. (183−188) However, several compounds have recently been described that could make the step into clinical practice in the future. For example, the antiprotozoal drug pentamidine has been identified as an outer membrane-permeabilizing agent. It was shown to potentiate the activity of typical Gram-positive-only drugs against Gram-negative bacteria in vitro and in a systemic Acinetobacter baumannii mouse infection model. Importantly, this activity was retained in colistin-resistant strains. (189,190) Since pentamidine has already been in clinical use for the treatment of trypanosomiasis, leishmaniasis, and babesiosis since 1937, its safety and side effects have been extensively assessed. Recent efforts have yielded lipophilic vancomycin analogues that were able to permeabilize both the inner and outer membrane of Gram-negative bacteria while retaining their ability to inhibit peptidoglycan activity. (191)

Attempts to fuse outer membrane-penetrating peptide sequences to the lantibiotic nisin, which by itself is not active against Gram-negative bacteria due to its inability to reach its inner membrane target, have resulted in hybrid molecules with significantly increased anti-Gram-negative activity. (192,193) A similar approach is the hybridization of antibiotics with the aminoglycoside tobramycin. (194) Tobramycin is known as a ribosome inhibitor but at higher concentrations primarily attacks and permeabilizes the outer membrane. (195,196) It has been conjugated with efflux pump inhibitors, (197) quinolones, (198,199) and the chelator cyclam. (200) The resulting conjugates turned out to be potent antibiotic adjuvants and increased the activity of tetracyclines, fluoroquinolones, and β-lactams against Gram-negative bacteria by increasing uptake and limiting efflux. This is achieved by a multifaceted mechanism involving outer membrane permeabilization, impairment of efflux pumps, and depolarization of the inner membrane. (117,194,197−200) Similar results have been obtained for tobramycin dimers. (201)

Another very interesting example are short peptide sequences derived from the cell cycle proteins FtsA and MreB from E. coli. These proteins bind to the cytoplasmic membrane with an amphipathic α helix motif. Peptides derived from these membrane-anchoring sequences not only display potent activity against E. coli and other Gram-negative bacteria but also significantly increase their outer membrane permeability. (186,202,203)

Few compounds are known that selectively permeabilize the outer membrane, and most known compounds also permeabilize the inner membrane. Such dual membrane activity can often be a sign for poor selectivity for bacteria, and side effects are likely. This is, for example, the case for colistin and polymyxin B and the reason why they are only employed as the last resort antibiotics for otherwise resistant infections. (98,204−206) However, colistin nonapeptide and polymyxin B hepta-, octa-, and nonapeptide are derivatives of these compounds that retain their membrane-permeabilizing but not antibacterial activity, indicating high selectivity. (184) Such derivatives, particularly polymyxin B nonapeptide, have been shown to act as strong potentiators of antibiotics with otherwise poor anti-Gram-negative activity. (184,207,208) At the same time, it is much less toxic than full-length polymyxin B. (184,209,210) While these properties have been demonstrated by many different studies, it is not used for combination therapy in the clinic. (211) However, a polymyxin derivative with similar properties as polymyxin B nonapeptide, NAB741, has been developed and successfully passed its first phase I clinical trial. (211) Compounds like polymyxin B nonapeptide or NAB741 hold great promise as potentiators of a wide range of antibiotics that would otherwise be ineffective against Gram-negative infections. It remains exciting to see how this type of compound proceeds in future clinical trials.

Sensitizers

A different strategy to enhance the performance of existing antibiotic drugs is to sensitize bacteria to their action. This can be achieved by inhibiting bacterial stress response systems that allow bacteria to adapt and survive antibiotic exposure (Figure 4B). Many studies on bacterial stress responses have proposed this as an option for future drug development, yet this has almost never been pursued. One exception is the bacterial SOS response to DNA damage. DNA damage is sensed by the RecA protein, which induces autoproteolysis of the LexA repressor, leading to derepression of DNA repair genes. It has been shown that genetically impairing this stress response mechanism leads to reversion of quinolone resistance in E. coli. (212) Few inhibitors of DNA repair have been verified so far. For example, p-coumaric acid was found to interfere with the DNA-binding ability of RecA in Listeria monocytogenes and increased the activity of ciprofloxacin against this pathogen. (213) Another study found that zinc inhibits the ability of RecA to bind to single-stranded DNA, suggesting a potential application for zinc ionophores. (214) However, the effectivity and cytotoxicity of zinc ionophores would depend on the external zinc concentration, (215) which may limit this approach to topical applications or targeted drug delivery and release approaches. A large-scale screen for inhibitors of LexA autoproteolysis has yielded promising lead structures for the inhibition of this step of SOS response activation. (216) Similarly, IMP-1700, a rationally designed inhibitor of DNA repair, was later verified to target the AddAB DNA repair complex and sensitized multidrug-resistant S. aureus to ciprofloxacin. (217)

Another example for this strategy was identified by a transposon screen for increased tobramycin sensitivity in Pseudomonas aeruginosa. This screen identified the two-component stress response system AmgRS as a potential target for combination therapy with aminoglycoside antibiotics. (218) It was later found that the RNA polymerase inhibitor rifampicin was also a potent inhibitor of this stress response system and potentiated the activity of aminoglycosides like tobramycin, amikacin, gentamycin, and neomycin against P. aeruginosa. (219,220)

A multitude of stress response systems have been identified that play a role for antibiotic adaptation and resistance, yet little effort has been put into identifying inhibitors of these systems to be used as antibiotic potentiators. In view of the urgent need for novel antibacterial strategies, this possibility deserves more attention.

Resistance Breakers

A similar strategy, yet much more exploited, is the direct targeting of bacterial resistance mechanisms (Table 4).

Table 4. Examples for Resistance-Breaking Compounds

resistance breaker	antibiotic	mechanism	ref
clavulanate^a	amoxicilline	β-lactamase inhibitor	(165,166)
avibactam^a	ceftazidime, ceftaroline, aztreonam	β-lactamase inhibitor	(221)
vaborbactam^a	Meropenem	β-lactamase inhibitor	(221)
tazobactam^a	ceftolozane	β-lactamase inhibitor	(221)
compound 1	amikacin	inhibitor of aminoglycoside-modifying enzymes	(222)
PAβN	erythromycin, chloramphenicol	efflux pump inhibitor	(223)
verapamil	bedaquiline, ofloxacin	efflux pump inhibitor	(224,225)
IMP-1700	quinolones	sensitizer (SOS response)	(212,217)
colistin^a	rifampin	permeabilizer	(226−228)
dispersin B	several possible	biofilm inhibitor	(229−231)
dehydrocrepenyc acid	several possible	inhibitor of horizontal gene transfer	(232)
streptazolin	several possible	immunomodulator	(233)

^{^a}

Combination in clinical use.

The most prominent example for this is the inhibition of β-lactamase activity (234) (Figure 4C). Having pioneered the field, it was the first resistance-breaking strategy to be applied in the clinic. It is also the only combination of antibiotic and potentiator in current clinical use apart from synergistic combinations with the outer membrane-permeabilizing peptides colistin and polymyxin B. The oldest combination of β-lactam antibiotic and β-lactamase inhibitor is amoxicillin–clavulanate, which was approved for clinical use in 1981. It is still in use today and remains the only one that is orally available. (235) Since then, several other β-lactamase inhibitors have been identified, and eight combinations are currently on the market: amoxicillin–clavulanate, ticarcillin–clavulanate, ampicillin–sulbactam, cefoperazone–sulbactam, piperacillin–tazobactam, ceftolozane–tazobactam, ceftazidime–avibactam, and Meropenem–vaborbactam. (221,235) Several other combinations are in different stages of clinical development. (221)

A similar strategy is the inhibition of aminoglycoside-modifying enzymes, which are responsible for the majority of cases of aminoglycoside resistance (Figure 4D). Different enzymes have been described that acetylate different sites of aminoglycoside antibiotics, (236) some of which are inhibited by Cu²⁺, Zn²⁺, and Cd²⁺ ions. (237) Inhibitors of these enzymes have been identified by molecular docking studies with virtual compound libraries and by screening libraries for in vitro enzyme inhibition. (222,238,239) One of these has been confirmed to restore the activity of amikacin against a resistant Acinetobacter baumannii strain. (222) However, none of these compounds is close to clinical development at the present time.

The most important intrinsic resistance mechanism, next to the outer membrane permeability barrier, is constituted by antibiotic efflux pumps. Particularly, Gram-negative bacteria possess different multidrug efflux pumps that can export a wide variety of antibiotics and antimicrobial molecules. The most prominent efflux pump type is the Gram-negative-specific resistance-nodulation-division (RND) superfamily, in particular the well-characterized AcrAB-TolC pump. (240) A wide variety of antibiotics can be the substrate of these export systems, and their overexpression leads to high level drug resistance. (240) This makes efflux pumps one of the biggest challenges in overcoming antibiotic resistance and at the same time an attractive target for resistance-breaking antibiotic potentiators (Figure 4E). Since the discovery of the very first efflux pump inhibitors reserpine and verapamil against the S. aureus efflux pump NorA in 1991, (240) a multitude of inhibitors have been identified for both Gram-positive and Gram-negative efflux pumps. Many of them have been found to increase the activity of drugs, which are normally ineffective due to active export. These molecules have been extensively reviewed elsewhere. (240−244) Despite these efforts, no efflux pump inhibitor has advanced to clinical development yet. Common limitations of these molecules appear to be a high toxicity for mammalian cells, low in vivo efficacy, and insufficient spectrum coverage. (240,245) More research into this topic is needed to fully understand how multidrug efflux pumps work and how they synergize with other resistance mechanisms, such as the outer membrane, to go forward with effective inhibitor design.

Prevention of Horizontal Gene Transfer

A very different strategy to target antibiotic resistance is inhibiting horizontal gene transfer. Target mutations are only one way for bacteria to become antibiotic resistant. The much more threatening possibility is the spread of resistance genes that are encoded on plasmids or other mobile genetic elements within a bacterial population. This is especially critical for otherwise slowly occurring resistance mechanisms like enzymatic resistance. (246) Importantly, the human (or animal) microbiota can act as a reservoir for resistance plasmids that may spread to pathogenic bacteria during infection. Thus, the administration of an inhibitor of horizontal gene transfer in combination with antibiotic treatment could decrease the incidence of resistance transfer from a reservoir to an infectious strain. (247) This is an interesting concept but remains to be tested in infection experiments. Several compounds have been identified that inhibit horizontal gene transfer, yet in the majority of cases, this activity turned out to be due to secondary effects. (248) However, a small number of specific inhibitors have been found. For example, unsaturated fatty acid species from tropical fruits and their synthetic derivatives were able to inhibit the transfer of the most important resistance-related plasmid types in several Gram-negative pathogens. (232,249) Likewise, a mutation of a competence-stimulating peptide from Streptococcus pneumoniae has resulted in peptide versions that reduced competence and, thus, horizontal gene transfer. (250) As mentioned earlier, zinc was able to inhibit the bacterial SOS response, which interestingly, also impaired horizontal gene transfer between enterobacteria. (214) Secretion systems could be a promising target for such molecules as well. Thus, the inhibition of type IV secretion, which is involved in conjugative DNA transfer, has been shown to be inhibited by small peptidomimetic compounds. (251) While more research is needed to verify the feasibility of these approaches in clinical settings, it is certainly an interesting new combination therapy strategy that deserves further exploration.

Biofilm Inhibitors

One big problem in the clinic is the production of biofilms by bacteria like S. aureus and P. aeruginosa, and biofilm inhibitors are potent potentiators for antibiotics used against such infections (Figure 4F). Strategies to prevent biofilm formation or disperse mature biofilms can commonly be divided into three categories: the inhibition of adhesion or extracellular matrix production, the inhibition of quorum sensing, and the dispersion of the extracellular matrix. (252) Several antimicrobial peptides, for example, LL-37, prevent adhesion of bacterial cells by inhibiting the initiation of biofilm production. (253) Furanones are structurally similar to the quorum sensing molecule N-acyl-homoserine-lactone and are thought to competitively inhibit binding to their cognate transcriptional regulator. (253) Several other analogues of quorum sensing molecules have been patented, yet studies on their clinical potential are yet to come. (254) The most prominent biofilm-dispersing agent is the glycoside hydrolase dispersin B, which directly targets the extracellular matrix. (230) Further small molecule inhibitors have been identified for all these mechanisms. (254−257)

Biofilm inhibitors are particularly relevant in the context of medical devices like catheters and of chronic lung infections, with P. aeruginosa being the most problematic pathogen due to its high intrinsic antibiotic resistance and the emergence of totally drug-resistant isolates. (258) Several compounds have been described that could be used against P. aeruginosa biofilms. Interestingly, biofilm-degrading enzymes have been shown to remain active when immobilized on a surface, suggesting future applications in medical device technologies. (259) Short glycans have been shown to disrupt P. aeruginosa biofilms and subsequently increase the efficacy of antibiotics against it. (260) The small peptide 1018 targets the stringent response (p)ppGpp signaling, which is involved in biofilm formation, and acts as a potent biofilm-dispersing agent not only for P. aeruginosa but also for other pathogens including Klebsiella pneumoniae and S. aureus. (261) Peptide 1018 also resulted in decreased virulence of P. aeruginosa in a murine skin infection model. (262) Similarly, small molecule quorum sensing inhibitors have been shown to increase the efficacy of tobramycin against P. aeruginosa in a foreign-body infection model in mice. (263) Micafungin, which inhibits the synthesis of the pseudomonal cell wall component 1,3-β-d-glucan, was demonstrated to prevent P. aeruginosa biofilm formation and improved the outcome of antibiotic therapy in P. aeruginosa-infected mice, particularly when combined with the fluoroquinolone levofloxacin. (264) Interestingly, when the fatty acid synthesis inhibitor triclosan, which has been commonly used in hygiene products like toothpaste, was applied together with aminoglycosides like tobramycin, a strong antibiofilm activity was observed. Neither of these compounds have an effect on biofilms by themselves, and the mechanism behind this adjuvant activity is unknown. (265) So far, no biofilm inhibitor has made the transition to the clinic, yet a number of preclinical studies show the promise of using such agents as antibiotic potentiators in the future.

Multidrug Approaches

Combination therapy approaches may involve more than two compounds. This is, for example, very common in tuberculosis treatment regimes, which often consist of a combination of rifampicin, isoniazid, ethambutol, and pyrazinamide (266) but has also been employed for other bacterial infections. (267) A newly emerging approach is the combination of an antibiotic with more than one potentiator. This has, for example, been explored for the combination of β-lactams with β-lactamase inhibitors and permeabilizers such as dimeric tobramycin and tobramycin–cyclam. (200,201) However, such combinations are not currently used in the clinic.

Challenges of Combination Therapy

To date, antibiotic combination therapy is rather a last resort for severe infections than a standard therapy option. It is normally only employed for infections with multiresistant bacteria that cannot be treated with monotherapy, for latent infections like tuberculosis, or for antibiotics that have a high risk of encountering resistance when applied alone, such as trimethoprim–sulfonamide or β-lactam−β-lactamase combinations. Just as multitarget antibiotics are more effective than single-target antibiotics, (267) combination therapy is superior over monotherapy in terms of patient outcomes, at least when it comes to infections with multiresistant pathogens. (268) The current developments on antibiotic adjuvants have shown great promise for new combination strategies being added to our clinically available repertoire soon. However, combination therapies also face challenges.

One important limitation is the development of clinically useful formulations and treatment regimes. Finding the right dosing, treatment intervals, and total treatment duration can already be challenging for single drugs and gets much more complicated with each additional drug added to the regime, since each individual drug has its own pharmacodynamic and -kinetic properties and its own side effects. Matching these to elicit the desired outcome in patients can be a serious challenge. (267,269) A solution for this limitation could be antibiotic hybrids as discussed in Designer Dual-Target Compounds. However, hybrid molecules may encounter other challenges like solubility and uptake. (125)

Another risk of combination therapy is antimicrobial resistance. While many empirical studies have found that drug combinations suppress resistance, (198,269−276) other studies have warned that under certain conditions antibiotic combinations might even promote faster resistance development. This is a particular concern for synergistic drug combinations. While they allow one to lower the dose and thus reduce side effects, (277,278) they come with an inherent risk of treatment failure through resistance: If resistance to one drug occurs, synergistic effects are lost, resulting in the low-dose exposure to a single antibiotic. (279−283) Even with nonsynergistic antibiotic combinations, the risk for increased resistance development is evident. A recent study found that the development of tolerance, i.e., the ability of bacteria to survive longer under antibiotic exposure without changing the antibiotic’s minimal inhibitory concentration, to one drug may promote the transmission of resistance to the second drug. (284) These unwanted effects of combination treatments seem to be due to the prolonged survival of bacteria and their exposure to sublethal antibiotic concentrations. Therefore, the concept of “hitting them fast and hard”, which has been proposed to be a key to successful antibiotic treatment, should be paid particular attention in combination regimes, even if lowering drug doses can be tempting to reduce adverse effects. (6,276)

Conclusion

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Many fascinating approaches have been and are currently being developed to target multiple molecules in bacterial cells. From antibiotics that have multiple downstream effects, true multitargeting compounds, and dual-activity hybrid molecules to combination approaches with antibiotic adjuvants, all of these strategies have shown a certain promise and give hope for one to see light at the end of the tunnel of antibiotic development. Recent research gives the concept of polypharmacology another dimension by designing antibiotic adjuvants that possess multiple mechanisms themselves, such as outer membrane permeabilization and efflux pump inhibition, which synergistically increase the intracellular antibiotic concentration. (197) While more research is needed to truly understand the complex mechanisms underlying some of these multiple activities, they have already taught us one important thing, namely, that we should not shy away from complex mechanisms and multiple targets but try to exploit their full potential for future drug development.

Author Information

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Corresponding Author
- Michaela Wenzel - Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden; http://orcid.org/0000-0001-9969-6113; Email: [email protected]
Author
- Declan Alan Gray - Newcastle University Biosciences Institute, Newcastle University, NE2 4HH Newcastle upon Tyne, United Kingdom
Author Contributions
Conceptualization, writing, and visualization: D.A.G. and M.W.
Notes
The authors declare no competing financial interest.

Acknowledgments

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M.W. received funding from Chalmers University of Technology and the Swedish Research Council (VR Starting Grant 2019-04521). The funders had no role in the design of the paper, in the writing of the manuscript, or in the decision to publish the results.

References

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Drlica, K., Malik, M., Kerns, R. J., and Zhao, X. (2008) Quinolone-Mediated Bacterial Death. Antimicrob. Agents Chemother. 52, 385– 392, DOI: 10.1128/AAC.01617-06
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Quinolone-mediated bacterial death
Drlica, Karl; Malik, Muhammad; Kerns, Robert J.; Zhao, Xilin
Antimicrobial Agents and Chemotherapy (2008), 52 (2), 385-392CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
A review. In the present review we consider cell death through a two-part "poison" hypothesis in which quinolones form reversible drug-topoisomerase-DNA complexes that subsequently lead to several types of irreversible (lethal) damage. Topics discussed include: quinolone-topoisomerase-DNA complexes; inhibition of DNA replication; SOS response and cell filamentation; toxin-antitoxin modules and programmed cell death; chromosome fragmentation; and destabilization of cleaved complexes.
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Chopra, I. (2007) Bacterial RNA Polymerase: A Promising Target for the Discovery of New Antimicrobial Agents. Curr. Opin. Investig. Drugs 8, 600– 607
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Bacterial RNA polymerase: a promising target for the discovery of new antimicrobial agents
Chopra, Ian
Current Opinion in Investigational Drugs (Thomson Scientific) (2007), 8 (8), 600-607CODEN: COIDAZ; ISSN:1472-4472. (Thomson Scientific)
A review. Prokaryotic DNA-dependent RNA polymerase (RNAP) is a multi-subunit enzyme responsible for transcription in bacteria. It is an important target for antibacterial chemotherapy because it is essential for bacterial growth and survival, and possesses features that distinguish it from mammalian counterparts. The rifamycins are currently the only class of RNAP inhibitors that have been approved for clin. use, and consequently bacterial RNAP remains relatively underexploited as an antibacterial drug target. However, improved understanding of the mol. basis of rifamycin action, revealed by X-ray crystallog. studies, has resulted in the development of new rifamycins, such as the benzoxazinorifamycins, with improved properties. Structural studies on other RNAP inhibitors have also been described, and a no. of older inhibitors now await detailed investigation to provide mol. explanations for their modes of action. New approaches have also resulted in the discovery of inhibitors of RNAP assembly. This review discusses various RNAP inhibitors in the context of their modes of action and potential development for therapeutic application. Opportunities for the discovery of new inhibitors are also discussed.
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Sköld, O. (2000) Sulfonamide Resistance: Mechanisms and Trends. Drug Resist. Updates 3, 155– 160, DOI: 10.1054/drup.2000.0146
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Sulfonamide resistance: Mechanisms and trends
Skold, Ola
Drug Resistance Updates (2000), 3 (3), 155-160CODEN: DRUPFW; ISSN:1368-7646. (Harcourt Publishers Ltd.)
A review with 42 refs. Sulfonamides were the first drugs acting selectively on bacteria which could be used systemically. Today they are infrequently used, in part due to widespread resistance. The target of sulfonamides, and the basis for their selectivity, is the enzyme dihydropteroate synthase (DHPS) in the folic acid pathway. Mammalian cells are not dependent on endogenous synthesis of folic acid and generally lack DHPS. Instead, they have a folate uptake system which most prokaryotes lack. Lab. mutants in the dhps(folP) gene can be easily isolated and show a trade off between sulfonamide resistance and DHPS enzyme performance. Clin. resistant mutants, however, have addnl. compensatory mutations in DHPS that allow it to function normally. In many pathogenic bacteria sulfonamide resistance is mediated by the horizontal transfer of foreign folP or parts of it. Clin. resistance in gram-neg. enteric bacteria is plasmid-borne and is effected by genes encoding alternative drug-resistance variants of the DHPS enzymes. Two such genes, sull and sul2, have been sequenced and are found at roughly the same frequency among clin. isolates. Remarkably, the corresponding DHPS enzymes show pronounced insensitivity to sulfonamides but normal binding to the p-aminobenzoic acid substrate, despite the close structural similarity between substrate and inhibitor.
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Yeaman, M. R. and Yount, N. Y. (2003) Mechanisms of Antimicrobial Peptide Action and Resistance. Pharmacol. Rev. 55, 27– 55, DOI: 10.1124/pr.55.1.2
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Mechanisms of antimicrobial peptide action and resistance
Yeaman, Michael R.; Yount, Nannette Y.
Pharmacological Reviews (2003), 55 (1), 27-55CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)
A review. Antimicrobial peptides have been isolated and characterized from tissues and organisms representing virtually every kingdom and phylum, ranging from prokaryotes to humans. Yet, recurrent structural and functional themes in mechanisms of action and resistance are obsd. among peptides of widely diverse source and compn. Biochem. distinctions among the peptides themselves, target vs. host cells, and the microenvironments in which these counterparts convene, likely provide for varying degrees of selective toxicity among diverse antimicrobial peptide types. Moreover, many antimicrobial peptides employ sophisticated and dynamic mechanisms of action to effect rapid and potent activities consistent with their likely roles in antimicrobial host defense. In balance, successful microbial pathogens have evolved multifaceted and effective countermeasures to avoid exposure to and subvert mechanisms of antimicrobial peptides. A clearer recognition of these opposing themes will significantly advance our understanding of how antimicrobial peptides function in defense against infection. Furthermore, this understanding may provide new models and strategies for developing novel antimicrobial agents, that may also augment immunity, restore potency or amplify the mechanisms of conventional antibiotics, and minimize antimicrobial resistance mechanisms among pathogens. From these perspectives, the intention of this review is to illustrate the contemporary structural and functional themes among mechanisms of antimicrobial peptide action and resistance.
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Brotz, H., Josten, M., Wiedemann, I., Schneider, U., Gotz, F., Bierbaum, G., and Sahl, H. G. (1998) Role of Lipid-Bound Peptidoglycan Precursors in the Formation of Pores by Nisin, Epidermin and Other Lantibiotics. Mol. Microbiol. 30, 317– 327, DOI: 10.1046/j.1365-2958.1998.01065.x
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Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics
Brotz, Heike; Josten, Michaele; Wiedemann, Imke; Schneider, Ursula; Gotz, Friedrich; Bierbaum, Gabriele; Sahl, Hans-Georg
Molecular Microbiology (1998), 30 (2), 317-327CODEN: MOMIEE; ISSN:0950-382X. (Blackwell Science Ltd.)
It is generally assumed that type A lantibiotics primarily kill bacteria by permeabilization of the cytoplasmic membrane. As previous studies had demonstrated that nisin interacts with the membrane-bound peptidoglycan precursors lipid I and lipid II, we presumed that this interaction could play a role in the pore formation process of lantibiotics. Using a thin-layer chromatog. system, the authors found that only nisin and epidermin, but no Pep5, can form a complex with [14C]-lipid II. Lipid II was then purified from Micrococcus luteus and incorporated into carboxyfluorescein-loaded liposomes made of phosphatidylcholine and cholesterol (1:1). Liposomes supplemented with 0.05 or 0.1 mol% of lipid II did not release any marker when treated with Pep5 or epilancin K7 (peptide concns. of up to 5 mol% were tested). In contrast, as little as 0.01 mol% of epidermin and 0.1 mol% of nisin were sufficient to induce rapid marker release; phosphatidylglycerol-contg. liposomes were even more susceptible. Controls with moenomycin-, undecaprenol- or dodecaprenolphosphate-doped liposomes demonstrated the specificity of the lantibiotics for lipid II. These results were correlated with intact cells in an in vivo model. M. luteus and Staphylococcus simulans were depleted of lipid II by preincubation with the lipopeptide ramoplanin and then tested for pore formation. When applied in concns. below the minimal inhibitory concn. (MIC) and up to 5-10 times the MIC, the pore formation by nisin and epidermin was blocked; at higher concns. of the lantibiotics the protective effect of ramoplanin disappeared. These results demonstrate that, in vitro and in vivo, lipid II serves as a docking mol. for nisin and epidermin, but not for Pep5 and epilancin K7, and thereby facilitates the formation of pores in the cytoplasmic membrane.
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Velkov, Y., Thompson, P., Azad, M., Roberts, K., and Bergen, P. (2019) History, Chemistry and Antibacterial Spectrum. In Polymyxin Antibiotics: From Laboratory Bench to Bedside (Li, J., Nation, R., and Kaye, K., Eds.) 1st ed., Vol. 1145, p 17, Spinger Nature, Switzerland AG, DOI: 10.1007/978-3-030-16373-0_3 .
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Tang, X.-J., Thibault, P., and Boyd, R. K. (1992) Characterisation of the Tyrocidine and Gramicidin Fractions of the Tyrothricin Complex from Bacillus Brevis Using Liquid Chromatography and Mass Spectrometry. Int. J. Mass Spectrom. Ion Processes 122, 153– 179, DOI: 10.1016/0168-1176(92)87015-7
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Characterization of the tyrocidine and gramicidin fractions of the tyrothricin complex from Bacillus brevis using liquid chromatography and mass spectrometry
Tang, Xue Jun; Thibault, Pierre; Boyd, Robert K.
International Journal of Mass Spectrometry and Ion Processes (1992), 122 (), 153-79CODEN: IJMPDN; ISSN:0168-1176.
The tyrothricin peptide complex, isolated from the fermn. broth of Bacillus brevis, is comprised of a basic fraction of cyclic decapeptides (the tyrocidines) and a neutral fraction composed of linear peptides (the gramicidins). Previously, 5 cyclic compds. (tyrocidines A-E) had been characterized by classical chem. procedures, and an addnl. 5 by M. Barber et al. (1992), who employed tandem mass spectrometric anal. of the crude mixt., together with an interpretative strategy based upon mass shifts related to simple amino acid substitutions. In the present work, initial profiling of the tyrothricin complex, using reverse phase liq. chromatog. (HPLC) coupled directly to tandem mass spectrometry via an ionspray interface, showed that the mixt. is extremely complex. Semi-preparative HPLC provided 32 fractions, some of which were still mixts., amenable to anal. by tandem mass spectrometry using the doubly-protonated peptide precursors produced by ionspray ionization. In this way the 10 previously known tyrocidines were confirmed, and structures of an addnl. 18 cyclic variants established with only minor uncertainties (e.g. present techniques could not distinguish Ile from Leu). Six linear gramicidins were known previously, and were confirmed in the present work. In addn., 3 previously unknown variants, of the Val1-gramicidins A, B and C, were discovered, in which the ethanolamide residue at the C-terminus is replaced by a propanolamide residue.
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Loll, P. J., Upton, E. C., Nahoum, V., Economou, N. J., and Cocklin, S. (2014) The High Resolution Structure of Tyrocidine A Reveals an Amphipathic Dimer. Biochim. Biophys. Acta, Biomembr. 1838, 1199– 1207, DOI: 10.1016/j.bbamem.2014.01.033
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The high resolution structure of tyrocidine A reveals an amphipathic dimer
Loll, Patrick J.; Upton, Elizabeth C.; Nahoum, Virginie; Economou, Nicoleta J.; Cocklin, Simon
Biochimica et Biophysica Acta, Biomembranes (2014), 1838 (5), 1199-1207CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Tyrocidine A (I), one of the 1st antibiotics ever to be discovered, is a cyclic decapeptide that binds to membranes of target bacteria, disrupting their integrity. I is active against a broad spectrum of Gram-pos. organisms, and has recently engendered interest as a potential scaffold for the development of new drugs to combat antibiotic-resistant pathogens. Here, the authors present the x-ray crystal structure of I at a resoln. of 0.95 Å. The structure revealed that tyrocidine forms an intimate and highly amphipathic homodimer made up of 4 β-strands that assoc. into a single, highly curved antiparallel β-sheet. The authors used surface plasmon resonance and K+ efflux assays to demonstrate that I bound tightly to mimetics of bacterial membranes with an apparent Kd of 10 μM, and efficiently permeabilized bacterial cells at concns. equal to and below the Kd. Using variant forms of I in which the fluorescent probe p-cyanophenylalanine had been inserted on either the polar or apolar face of the mol., the authors performed fluorescence quenching expts., using both water-sol. and membrane-embedded quenchers. The quenching results, together with the structure, strongly support a membrane assocn. model in which the convex, apolar face of the I β-sheet was oriented toward the membrane interior, while the concave, polar face was presented to the aq. phase.
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Munyuki, G., Jackson, G. E., Venter, G. A., Kover, K. E., Szilagyi, L., Rautenbach, M., Spathelf, B. M., Bhattacharya, B., and van der Spoel, D. (2013) Beta-Sheet Structures and Dimer Models of the Two Major Tyrocidines, Antimicrobial Peptides from Bacillus Aneurinolyticus. Biochemistry 52, 7798– 7806, DOI: 10.1021/bi401363m
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β-Sheet structures and dimer models of the two major tyrocidines, antimicrobial peptides from Bacillus aneurinolyticus
Munyuki, Gadzikano; Jackson, Graham E.; Venter, Gerhard A.; Kover, Katalin E.; Szilagyi, Laszlo; Rautenbach, Marina; Spathelf, Barbara M.; Bhattacharya, Bhaswati; van der Spoel, David
Biochemistry (2013), 52 (44), 7798-7806CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
The structures of two major tyrocidines, antibiotic peptides from Bacillus aneurinolyticus, in an aq. environment were studied using NMR spectroscopy, restrained mol. dynamics (MD), CD, and mass spectrometry. TrcA and TrcC formed β-structures in an aq. environment. Hydrophobic and hydrophilic residues were not totally sepd. into nonpolar and polar faces of the peptides, indicating that tyrocidines have low amphipathicity. In all the β-structures, residues Trp4/Phe4 and Orn9 were on the same face. The ability of the peptides to form dimers in aq. environment was studied by replica exchange MD simulations. Both peptides readily dimerize, and predominant complex structures were characterized through cluster anal. The peptides formed dimers by either assocg. sideways or stacking on top of each other. Dimers formed through sideways assocn. were mainly stabilized by hydrogen bonding, while the other dimers were stabilized by hydrophobic interactions. The ability of tyrocidine peptides to form different types of dimers with different orientations suggests that they can form larger aggregates, as well.
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Leussa, A. N.-N. and Rautenbach, M. (2014) Detailed SAR and PCA of the Tyrocidines and Analogues towards Leucocin A-Sensitive and Leucocin A-Resistant Listeria Monocytogenes. Chem. Biol. Drug Des. 84, 543– 557, DOI: 10.1111/cbdd.12344
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Detailed SAR and PCA of tyrocidines and analogs towards leucocin A-sensitive and leucocin A-resistant Listeria monocytogenes
Leussa, Adrienne Nyango-Nkeh; Rautenbach, Marina
Chemical Biology & Drug Design (2014), 84 (5), 543-557CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
The tyrocidines, antimicrobial cyclic decapeptides from Bacillus aneurinolyticus, have potent activity with drug/disinfectant potential, specifically against Listeria monocytogenes. The tyrocidine activity is dependent on an amphipathic balance. Structure-activity relationship (SAR) anal. combined with principal component anal. showed the best activity correlation with hydropathy and solvent accessible vol. (hydrophobicity parameters), Mr and mol. vol. (steric/size parameters), coupled with rigid sequence and charge prerequisites. For potent activity against L. monocytogenes strains, there is a prerequisite for a Tyr or Phe in the (W/F)(w/f)NQ(Y/F/W) sequence of the variable pentapeptide and ornithine (Orn, O) as cationic residue in the conserved V(K/O)LfP pentapeptide, particularly with Trp in the arom. dipeptide moiety of the variable pentapeptide. The roles of Trp and Orn in the tyrocidines were confirmed with the most active peptide, tyrocidine B (TrcB) contg. Orn and a Trp-D-Phe in the arom. dipeptide moiety. However, a novel analog with a trimethylated ornithine and Phe-D-Phe showed an activity rivalling that of TrcB. The results emphasize that activity is dictated by an interplay between the character of the arom. residues in the variable pentapeptide and the cationic residue. Any residue change resulting in tighter membrane/cell wall interaction is likely to trap tyrocidines and impede their mechanism of action.
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Spathelf, B. M. and Rautenbach, M. (2009) Anti-Listerial Activity and Structure-Activity Relationships of the Six Major Tyrocidines, Cyclic Decapeptides from Bacillus Aneurinolyticus. Bioorg. Med. Chem. 17, 5541– 5548, DOI: 10.1016/j.bmc.2009.06.029
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Anti-listerial activity and structure-activity relationships of the six major tyrocidines, cyclic decapeptides from Bacillus aneurinolyticus
Spathelf, Barbara M.; Rautenbach, Marina
Bioorganic & Medicinal Chemistry (2009), 17 (15), 5541-5548CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
Six major tyrocidines, purified from the antibiotic tyrothricin complex produced by Bacillus aneurinolyticus, showed significant lytic and growth inhibitory activity towards the Gram-pos. bacteria Micrococcus luteus and Listeria monocytogenes, but not against the Gram-neg. Escherichia coli. The isolated natural tyrocidines were more active against the leucocin A (antimicrobial peptide) resistant strain, L. monocytogenes B73-MR1, than the sensitive L. monocytogenes B73 strain. Remarkably similar structure-activity trends toward the three Gram-pos. bacteria were found between growth inhibition and different physicochem. parameters (soln. amphipathicity, theor. lipophilicity, side-chain surface area and mass-over-charge ratio).
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Wenzel, M., Rautenbach, M., Vosloo, J. A., Siersma, T., Aisenbrey, C. H. M., Zaitseva, E., Laubscher, W. E., van Rensburg, W., Behrends, J., Bechinger, B., and Hamoen, L. W. (2018) The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S. mBio 9, e00802-18 DOI: 10.1128/mBio.00802-18
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Palm, J., Fuchs, K., Stammer, H., Schumacher-Stimpfl, A., and Milde, J. (2018) Efficacy and Safety of a Triple Active Sore Throat Lozenge in the Treatment of Patients with Acute Pharyngitis: Results of a Multi-Centre, Randomised, Placebo-Controlled, Double-Blind, Parallel-Group Trial (DoriPha). Int. J. Clin. Pract. 72, e13272 DOI: 10.1111/ijcp.13272
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Bosscha, M. I., van Dissel, J. T., Kuijper, E. J., Swart, W., and Jager, M. J. (2004) The Efficacy and Safety of Topical Polymyxin B, Neomycin and Gramicidin for Treatment of Presumed Bacterial Corneal Ulceration. Br. J. Ophthalmol. 88, 25– 28, DOI: 10.1136/bjo.88.1.25
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The efficacy and safety of topical polymyxin B, neomycin and gramicidin for treatment of presumed bacterial corneal ulceration
Bosscha M I; van Dissel J T; Kuijper E J; Swart W; Jager M J
The British journal of ophthalmology (2004), 88 (1), 25-8 ISSN:0007-1161.
AIM: To evaluate the clinical efficacy and safety of topical polymyxin B, neomycin, and gramicidin for the treatment of suspected bacterial corneal ulceration at the Leiden University Medical Center. METHODS: Patients with a diagnosis of a suspected bacterial corneal ulcer between April 1995 and February 2002 were retrospectively identified and reviewed; clinical and microbiological features and response to therapy were analysed. All patients were treated with Polyspectran eye drops. RESULTS: In total, 91 patients were included in this analysis. Bacteriological cultures of 46 patients (51%) were positive and revealed 51 microorganisms. Staphylococcus aureus (29.4%) and Pseudomonas aeruginosa (23.5%) were the most frequently encountered bacteria. Eighteen patients switched therapy before complete healing of the corneal ulceration, four patients were lost to follow up. Of the 69 patients who completed Polyspectran treatment, re-epithelialisation occurred in 68 patients (99%) and on average took 12.6 (median 8) days. Among 91 patients, there were four perforations and one evisceration. Seven toxic or allergic reactions were reported. CONCLUSION: This study shows that the combination of polymyxin B, neomycin, and gramicidin is an effective and safe treatment of suspected corneal ulceration.
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Jia, J., Zhu, F., Ma, X., Cao, Z. W., Li, Y. X., and Chen, Y. Z. (2009) Mechanisms of Drug Combinations: Interaction and Network Perspectives. Nat. Rev. Drug Discovery 8, 111, DOI: 10.1038/nrd2683
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Mechanisms of drug combinations: interaction and network perspectives
Jia, Jia; Zhu, Feng; Ma, Xiaohua; Cao, Zhiwei W.; Li, Yixue X.; Chen, Yu Zong
Nature Reviews Drug Discovery (2009), 8 (2), 111-128CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
A review. Understanding the mol. mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous anal. methods and for which relevant mol. interaction profiles of the drugs involved are available. Anal. of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of mol. interaction profiles in the discovery of novel multicomponent therapies.
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Reddy, A. S. and Zhang, S. (2013) Polypharmacology: Drug Discovery for the Future. Expert Rev. Clin. Pharmacol. 6, 41– 47, DOI: 10.1586/ecp.12.74
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Polypharmacology: drug discovery for the future
Reddy, A. Srinivas; Zhang, Shuxing
Expert Review of Clinical Pharmacology (2013), 6 (1), 41-47CODEN: ERCPAG; ISSN:1751-2433. (Expert Reviews Ltd.)
A review. In recent years, even with remarkable scientific advancements and a significant increase of global research and development spending, drugs are frequently withdrawn from markets. This is primarily due to their side effects or toxicities. Drug mols. often interact with multiple targets, coined as polypharmacol., and the unintended drug-target interactions could cause side effects. Polypharmacol. remains one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective, but less toxic, therapeutic agents. This review outlines the latest progress and challenges in polypharmacol. studies.
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Müller, A., Wenzel, M., Strahl, H., Grein, F., Saaki, T. N. V, Kohl, B., Siersma, T., Bandow, J. E., Sahl, H.-G., Schneider, T., and Hamoen, L. W. (2016) Daptomycin Inhibits Cell Envelope Synthesis by Interfering with Fluid Membrane Microdomains. Proc. Natl. Acad. Sci. U. S. A. 113, E7077– E7086, DOI: 10.1073/pnas.1611173113
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Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains
Mueller, Anna; Wenzel, Michaela; Strahl, Henrik; Grein, Fabian; Saaki, Terrens N. V.; Kohl, Bastian; Siersma, Tjalling; Bandow, Julia E.; Sahl, Hans-Georg; Schneider, Tanja; Hamoen, Leendert W.
Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (45), E7077-E7086CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Daptomycin is a highly efficient last-resort antibiotic that targets the bacterial cell membrane. Despite its clin. importance, the exact mechanism by which daptomycin kills bacteria is not fully understood. Different expts. have led to different models, including (i) blockage of cell wall synthesis, (ii) membrane pore formation, and (iii) the generation of altered membrane curvature leading to aberrant recruitment of proteins. To det. which model is correct, the authors carried out a comprehensive mode-of-action study using the model organism Bacillus subtilis and different assays, including proteomics, ionomics, and fluorescence light microscopy. The authors found that daptomycin causes a gradual decrease in membrane potential but does not form discrete membrane pores. Although the authors found no evidence for altered membrane curvature, the authors confirmed that daptomycin inhibits cell wall synthesis. Interestingly, using different fluorescent lipid probes, the authors showed that binding of daptomycin led to a drastic rearrangement of fluid lipid domains, affecting overall membrane fluidity. Importantly, these changes resulted in the rapid detachment of the membrane-assocd. lipid II synthase MurG and the phospholipid synthase PlsX. Both proteins preferentially colocalize with fluid membrane microdomains. Delocalization of these proteins presumably is a key reason why daptomycin blocks cell wall synthesis. Finally, clustering of fluid lipids by daptomycin likely causes hydrophobic mismatches between fluid and more rigid membrane areas. This mismatch can facilitate proton leakage and may explain the gradual membrane depolarization obsd. with daptomycin. Targeting of fluid lipid domains has not been described before for antibiotics and adds another dimension to the authors' understanding of membrane-active antibiotics.
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Hachmann, A. B., Sevim, E., Gaballa, A., Popham, D. L., Antelmann, H., and Helmann, J. D. (2011) Reduction in Membrane Phosphatidylglycerol Content Leads to Daptomycin Resistance in Bacillus Subtilis. Antimicrob. Agents Chemother. 55, 4326– 4337, DOI: 10.1128/AAC.01819-10
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Reduction in membrane phosphatidylglycerol content leads to daptomycin resistance in Bacillus subtilis
Hachmann, Anna-Barbara; Sevim, Elif; Gaballa, Ahmed; Popham, David L.; Antelmann, Haike; Helmann, John D.
Antimicrobial Agents and Chemotherapy (2011), 55 (9), 4326-4337CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
Daptomycin (DAP) is a cyclic lipopeptide that disrupts the functional integrity of the cell membranes of Gram-pos. bacteria in a Ca2+-dependent manner. Here, the authors present genetic, genomic, and phenotypic analyses of an evolved DAP-resistant isolate, DapR1, from the model bacterium Bacillus subtilis 168. DapR1 was obtained by serial passages with increasing DAP concns., is 30-fold more resistant than the parent strain, and displays cross-resistance to vancomycin, moenomycin, and bacitracin. DapR1 is characterized by aberrant septum placement, notably thickened peptidoglycan at the cell poles, and pleiotropic alterations at both the transcriptome and proteome levels. Genome sequencing of DapR1 revealed 44 point mutations, 31 of which change protein sequences. An intermediate isolate that was 20-fold more resistant to DAP than the wild type had only three of these point mutations: mutations affecting the cell shape modulator gene mreB, the stringent response gene relA, and the phosphatidylglycerol synthase gene pgsA. Genetic reconstruction studies indicated that the pgsA(A64V) allele is primarily responsible for DAP resistance. Allelic replacement with wild-type pgsA restored DAP sensitivity to wild-type levels. The addnl. point mutations in the evolved strain may contribute further to DAP resistance, serve to compensate for the deleterious effects of altered membrane compn., or represent neutral changes. These results suggest a resistance mechanism by which reduced levels of phosphatidylglycerol decrease the net neg. charge of the membrane, thereby weakening interaction with the pos. charged Ca2+-DAP complex.
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Reynolds, P. E. (1989) Structure, Biochemistry and Mechanism of Action of Glycopeptide Antibiotics. Eur. J. Clin. Microbiol. Infect. Dis. 8, 943– 950, DOI: 10.1007/BF01967563
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Structure, biochemistry, and mechanism of action of glycopeptide antibiotics
Reynolds, P. E.
European Journal of Clinical Microbiology & Infectious Diseases (1989), 8 (11), 943-50CODEN: EJCDEU; ISSN:0934-9723.
A review with 27 refs. discussing the unique mechanism of action by which peptidoglycan antibiotics inhibit a late stage in bacterial cell wall peptidoglycan synthesis.
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Singh, M., Chang, J., Coffman, L., and Kim, S. J. (2017) Hidden Mode of Action of Glycopeptide Antibiotics: Inhibition of Wall Teichoic Acid Biosynthesis. J. Phys. Chem. B 121, 3925– 3932, DOI: 10.1021/acs.jpcb.7b00324
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Hidden Mode of Action of Glycopeptide Antibiotics: Inhibition of Wall Teichoic Acid Biosynthesis
Singh, Manmilan; Chang, James; Coffman, Lauryn; Kim, Sung Joon
Journal of Physical Chemistry B (2017), 121 (16), 3925-3932CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
Glycopeptide antibiotics inhibit the peptidoglycan biosynthesis in Gram-pos. bacteria by targeting lipid II. This prevents the recycling of bactoprenol phosphate, the lipid transporter that is shared by peptidoglycan and wall teichoic acid biosyntheses. In this study, we investigate the effects of glycopeptide antibiotics on peptidoglycan and wall teichoic acid biosynthesis. The incorporation of D-[1-13C]alanine, D-[15N]alanine, and L-[1-13C]lysine into peptidoglycan and wall teichoic acid in intact whole cells of Staphylococcus aureus were measured using 13C{15N} and 15N{13C} rotational-echo double resonance NMR. S. aureus treated with oritavancin and vancomycin at sub-minimal inhibitory concns. exhibit a large redn. in D-Ala incorporation into wall teichoic acid, but without changes to the peptidoglycan crosslinks or the stem-links. Thus, sequestration of bactoprenol phosphate by glycopeptide antibiotics resulted in inhibition of D-Ala incorporation into the wall teichoic acid prior to the inhibition of peptidoglycan biosynthesis. Our finding shows that S. aureus respond to glycopeptide-induced cell wall stress by routing all available D-Ala to the peptidoglycan biosynthesis, at the cost of reducing the wall teichoic acid biosynthesis.
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Stone, K. J. and Strominger, J. L. (1971) Mechanism of Action of Bacitracin: Complexation with Metal Ion and C55-Isoprenyl Pyrophosphate. Proc. Natl. Acad. Sci. U. S. A. 68, 3223– 3227, DOI: 10.1073/pnas.68.12.3223
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Mechanism of action of bacitracin. Complexation with metal ion and C55-isoprenyl pyrophosphate
Stone, K. John; Strominger, Jack L.
Proceedings of the National Academy of Sciences of the United States of America (1971), 68 (12), 3223-7CODEN: PNASA6; ISSN:0027-8424.
Bacitracin inhibition of the enzymic dephosphorylation of C55-isoprenyl pyrophosphate [31867-59-1] was abolished by the addn. of chelating agents such as EDTA [60-00-4] (.sim.10-4M). If the chelating agent is added after a preincubation of bacitracin with a divalent cation (magnesium ion [7439-95-4], calcium ion [7440-70-2], etc.) and the lipid substrate, then its addn. has little effect,indicating that bacitracin, metal ion, and C55-isoprenyl pyrophosphate form a complex. Monovalent cations are ineffective in complex formation. The metal ion may serve as a bridge between the antibiotic and substrate.
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Tu, Y. and McCalla, D. R. (1975) Effect of Activated Nitrofurans on DNA. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 402, 142– 149, DOI: 10.1016/0005-2787(75)90032-5
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Effect of activated nitrofurans on DNA
Tu, Yu; McCalla, D. R.
Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1975), 402 (2), 142-9CODEN: BBNPAS; ISSN:0005-2787.
Enzymically activated nitrofurazone (I) [59-87-0] reacted with covalently closed circular DNA (derived from Escherichia coli minicells carrying λdv) to give ≥2 kinds of damage: breaks which were detected on neutral sucrose gradients and alkali-labile lesions in DNA which were converted to breaks when the DNA was subsequently treated with alkali. DNA, isolated from minicells exposed to the drug, also contained lesions which were converted to breaks upon treatment with endonuclease prepns. obtained from Micrococcus luteus. Minicells repaired both breaks and nuclease-susceptible lesions within 2 hr but did not repair alkali labile lesions within that time. Expts. with 3 other nitrofurans showed that there were considerable differences in the degree to which DNA was damaged by activated metabolites of various derivs. and that the potency of the compds. as mutagens and carcinogens was correlated with the amt. of damage caused to minicell DNA.
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Wenzel, M., Dekker, M. P., Wang, B., Burggraaf, M. J., Bitter, W., van Weering, J. R. T., and Hamoen, L. W. (2019) New Flat Embedding Method for Transmission Electron Microscopy Reveals an Unknown Mechanism of Tetracycline. bioRxiv 820191, DOI: 10.1101/820191
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Brötz-Oesterhelt, H., Beyer, D., Kroll, H.-P., Endermann, R., Ladel, C., Schroeder, W., Hinzen, B., Raddatz, S., Paulsen, H., Henninger, K., Bandow, J. E., Sahl, H.-G., and Labischinski, H. (2005) Dysregulation of Bacterial Proteolytic Machinery by a New Class of Antibiotics. Nat. Med. 11, 1082– 1087, DOI: 10.1038/nm1306
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Dysregulation of bacterial proteolytic machinery by a new class of antibiotics
Brotz-Oesterhelt Heike; Beyer Dieter; Kroll Hein-Peter; Endermann Rainer; Ladel Christoph; Schroeder Werner; Hinzen Berthold; Raddatz Siegfried; Paulsen Holger; Henninger Kerstin; Bandow Julia E; Sahl Hans-Georg; Labischinski Harald
Nature medicine (2005), 11 (10), 1082-7 ISSN:1078-8956.
Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.
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Sass, P., Josten, M., Famulla, K., Schiffer, G., Sahl, H.-G., Hamoen, L., and Brotz-Oesterhelt, H. (2011) Antibiotic Acyldepsipeptides Activate ClpP Peptidase to Degrade the Cell Division Protein FtsZ. Proc. Natl. Acad. Sci. U. S. A. 108, 17474– 17479, DOI: 10.1073/pnas.1110385108
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Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ
Sass, Peter; Josten, Michaele; Famulla, Kirsten; Schiffer, Guido; Sahl, Hans-Georg; Hamoen, Leendert; Broetz-Oesterhelt, Heike
Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (42), 17474-17479, S17474/1-S17474/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The worldwide spread of antibiotic-resistant bacteria has lent urgency to the search for antibiotics with new modes of action that are devoid of preexisting cross-resistances. We previously described a unique class of acyldepsipeptides (ADEPs) that exerts prominent antibacterial activity against Gram-pos. pathogens including streptococci, enterococci, as well as multi-drug-resistant Staphylococcus aureus. Here, we report that ADEP prevents cell division in Gram-pos. bacteria and induces strong filamentation of rod-shaped Bacillus subtilis and swelling of coccoid S. aureus and Streptococcus pneumoniae. It emerged that ADEP treatment inhibits septum formation at the stage of Z-ring assembly, and that central cell division proteins delocalize from midcell positions. Using in vivo and in vitro studies, we show that the inhibition of Z-ring formation is a consequence of the proteolytic degrdn. of the essential cell division protein FtsZ. ADEP switches the bacterial ClpP peptidase from a regulated to an uncontrolled protease, and it turned out that FtsZ is particularly prone to degrdn. by the ADEP-CIpP complex. By preventing cell division, ADEP inhibits a vital cellular process of bacteria that is not targeted by any therapeutically applied antibiotic so far. Their unique multi-faceted mechanism of action and antibacterial potency makes them promising lead structures for future antibiotic development.
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Deoghare, S. (2013) Bedaquiline: A New Drug Approved for Treatment of Multidrug-Resistant Tuberculosis. Indian J. Pharmacol. 45, 536– 537, DOI: 10.4103/0253-7613.117765
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Bedaquiline: a new drug approved for treatment of multidrug-resistant tuberculosis
Deoghare Shashank
Indian journal of pharmacology (2013), 45 (5), 536-7 ISSN:.
There is no expanded citation for this reference.
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Chopra, I. and Roberts, M. (2001) Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance. Microbiol. Mol. Biol. Rev. 65, 232– 60, DOI: 10.1128/MMBR.65.2.232-260.2001
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Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance
Chopra, Ian; Roberts, Marilyn
Microbiology and Molecular Biology Reviews (2001), 65 (2), 232-260CODEN: MMBRF7; ISSN:1092-2172. (American Society for Microbiology)
A review is given. Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-pos. and gram-neg. bacteria, chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites. They are inexpensive antibiotics, which were used extensively in the prophylaxis and therapy of human and animal infections and also at subtherapeutic levels in animal feed as growth promoters. The 1st tetracycline-resistant bacterium, Shigella dysenteriae, was isolated in 1953. Tetracycline resistance now occurs in an increasing no. of pathogenic, opportunistic, and commensal bacteria. The presence of tetracycline-resistant pathogens limits the use of these agents in treatment of disease. Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Many of these genes are assocd. with mobile plasmids or transposons and can be distinguished from each other using mol. methods including DNA-DNA hybridization with oligonucleotide probes and DNA sequencing. A limited no. of bacteria acquire resistance by mutations, which alter the permeability of the outer membrane porins and/or lipopolysaccharides in the outer membrane, change the regulation of innate efflux systems, or alter the 16S rRNA. New tetracycline derivs. are being examd., although their role in treatment is not clear. Changing the use of tetracyclines in human and animal health as well as in food prodn. is needed if the authors are to continue to use this class of broad-spectrum antimicrobials through the present century.
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Teuber, M. and Bader, J. (1976) Action of Polymyxin B on Bacterial Membranes. Binding Capacities for Polymyxin B of Inner and Outer Membranes Isolated from Salmonella Typhimurium G30. Arch. Microbiol. 109, 51– 58, DOI: 10.1007/BF00425112
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Action of polymyxin B on bacterial membranes. Binding capacities for polymyxin B of inner and outer membranes isolated from Salmonella typhimurium G30
Teuber, Michael; Bader, Johann
Archives of Microbiology (1976), 109 (1-2), 51-8CODEN: AMICCW; ISSN:0302-8933.
Polymyxin B sulfate [1405-20-5] was absorbed within 60 sec by isolated inner (cytoplasmic) and outer membranes from S. typhimurium. The sigmoidal binding isotherms indicated satn. of inner and outer membranes with approx. 30 and 60 nmoles polymyxin B bound per mg membrane, resp. Based on the known lipid contents of these membranes, a calcn. of the theor. binding capacities yielded almost identical values if lipopolysaccharide, phosphatidylglycerol, and cardiolipin are assumed to function as the actual binding sites for the antibiotic in the isolated membranes. The excellent agreement between theor. evaluation and exptl. detn. of polymyxin B-binding capacities indicated that the named anionic compds. are the chemoreceptors for the cationic antibiotic. This was further substantiated by very similar binding and killing kinetics of polymyxin B.
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Bohg, A. and Ristow, H. (1987) Tyrocidine-Induced Modulation of the DNA Conformation in Bacillus Brevis. Eur. J. Biochem. 170, 253– 258, DOI: 10.1111/j.1432-1033.1987.tb13693.x
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Tyrocidine-induced modulation of the DNA conformation in Bacillus brevis
Bohg, Anne; Ristow, Hansjuergen
European Journal of Biochemistry (1987), 170 (1/2), 253-8CODEN: EJBCAI; ISSN:0014-2956.
Using the [3H]trimethylpsoralen photobinding method, a decrease in unrestrained torsional tension of DNA was detected in B. brevis when they had entered the sporulation phase. This decrease in superhelicity was found in cells which synthesized the peptide antibiotic tyrocidine and which were stimulated to sporulate. Fluctuations in superhelicity probably reflect a highly complicated picture of tension-relaxing and tension-inducing activities. Addn. of tyrocidine to vegetative cells reduced by one-half the torsional tension from DNA, whereas ethidium bromide relaxes DNA completely. Cross-links between DNA and tyrocidine were introduced with UV light in vitro and in vivo, indicating that the modulation of the DNA conformation in the cell may in fact be due to a DNA-tyrocidine interaction. In a growing B. brevis culture exogenous [3H]tyorcidine could only be photobound to DNA after the cells had entered the sporulation phase. These results could mean that the peptide antibiotic tyrocidine is active in B. brevis on the DNA level as one regulatory factor controlling DNA functions.
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Ristow, H., Schazschneider, B., Vater, J., and Kleinkauf, H. (1975) Some Characteristics of the DNA-Tyrocidine Complex and a Possible Mechanism of the Gramicidin Action. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 414, 1– 8, DOI: 10.1016/0005-2787(75)90120-3
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Characteristics of the DNA-tyrocidine complex and a possible mechanism of the gramicidin action
Ristow, H.; Schazschneider, B.; Vater, J.; Kleinkauf, H.
Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1975), 414 (1), 1-8CODEN: BBNPAS; ISSN:0005-2787.
The cyclic peptide antibiotic tyrocidine which is known to inhibit RNA synthesis in vitro by forming a complex with the DNA induced hypochromicity of the DNA. The complex dissocd. at elevated temps. which are below the melting temp. of the DNA. The linear peptide antibiotic gramicidin which is known to reverse the inhibitory effect of tyrocidine did not bind to DNA and did not induce hypochromicity of the DNA. However, the DNA-tyrocidine complex dissocd. at lower temps. when gramicidin was present. Thus gramicidin apparently weakens the binding of tyrocidine to DNA. The presence of DNA quenched the fluorescence of tyrocidine but not that of gramicidin. This quenching of tyrocidine fluorescence was reduced in the presence of gramicidin. Tyrocidine inhibited transcription of single-stranded DNA as well. This inhibition was also reversed by gramicidin. Thus, the action of the peptides is not dependent on a double-stranded DNA conformation.
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Weinkle, A. P., Doktor, V., and Emer, J. (2015) Update on the Management of Rosacea. Clin., Cosmet. Invest. Dermatol. 8, 159– 177, DOI: 10.2147/CCID.S58940
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Update on the management of rosacea
Weinkle, Allison P.; Doktor, Vladyslava; Emer, Jason
Clinical, Cosmetic and Investigational Dermatology (2015), 8 (), 159-177CODEN: CCIDCL; ISSN:1178-7015. (Dove Medical Press Ltd.)
Refining diagnostic criteria has identified key characteristics differentiating rosacea, a chronic skin disorder, from other common cutaneous inflammatory conditions. The current classification system developed by the National Rosacea Society Expert Committee consists of erythematotelangiectatic, papulopustular, phymatous, and ocular subtypes. Each subtype stands as a unique entity among a spectrum, with characteristic symptoms and phys. findings, along with an intricate pathophysiol. The main treatment modalities for rosacea include topical, systemic, laser, and light therapies. Topical brimonidine tartrate gel and calcineurin inhibitors are at the forefront of topical therapies, alone or in combination with traditional therapies such as topical metronidazole or azelaic acid and oral tetracyclines or isotretinoin. Vascular laser and intense pulsed light therapies are beneficial for the erythema and telangiectasia, as well as the symptoms (itching, burning, pain, stinging, swelling) of rosacea. Injectable botulinum toxin, topical ivermectin, and microsecond long-pulsed neodymium-yttrium aluminum garnet laser are emerging therapies that may prove to be extremely beneficial in the future. Once a debilitating disorder, rosacea has become a well known and manageable entity in the setting of numerous emerging therapeutic options. Herein, we describe the treatments currently available and give our opinions regarding emerging and combination therapies.
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Del Rosso, J. Q. and Schmidt, N. F. (2010) A Review of the Anti-Inflammatory Properties of Clindamycin in the Treatment of Acne Vulgaris. Cutis 85, 15– 24
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A review of the anti-inflammatory properties of clindamycin in the treatment of acne vulgaris
Del Rosso James Q; Schmidt Nicholas F
Cutis (2010), 85 (1), 15-24 ISSN:0011-4162.
This article reviews anti-inflammatory properties of clindamycin, which is often used topically for the management of acne vulgaris, usually in combination with other agents. The efficacy of clindamycin in acne treatment has been shown to be sustained for more than 3 decades. It is likely that anti-inflammatory effects play an important role in the therapeutic activity of topical clindamycin.
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Goihman-Yahr, M., Pari, T., George, S., Jacob, M., Chandi, S. M., Pulimood, S., and Rajagopalan, B. (1996) Malignant Pyoderma Responding to Clofazimine. Int. J. Dermatol. 35, 757, DOI: 10.1111/j.1365-4362.1996.tb00660.x
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Seukeran, D. C., Stables, G. I., Cunliffe, W. J., and Sheehan-Dare, R. A. (1999) The Treatment of Acne Agminata with Clofazimine. Br. J. Dermatol. 141, 596– 597, DOI: 10.1046/j.1365-2133.1999.03084.x
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The treatment of acne agminata with clofazimine
Seukeran D C; Stables G I; Cunliffe W J; Sheehan-Dare R A
The British journal of dermatology (1999), 141 (3), 596-7 ISSN:0007-0963.
There is no expanded citation for this reference.
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Gomez-De la Fuente, E., del Rio, R., Rodriguez, M., Guerra, A., Rodriguez-Peralto, J. L., and Iglesias, L. (2000) Granuloma Faciale Mimicking Rhinophyma: Response to Clofazimine. Acta Derm.-Venereol. 80, 144
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Granuloma faciale mimicking rhinophyma: response to clofazimine
Gomez-de la Fuente E; del Rio R; Rodriguez M; Guerra A; Rodriguez-Peralto J L; Iglesias L
Acta dermato-venereologica (2000), 80 (2), 144 ISSN:0001-5555.
There is no expanded citation for this reference.
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Prendiville, J. S., Logan, R. A., and Russell-Jones, R. (1988) A Comparison of Dapsone with 13-Cis Retinoic Acid in the Treatment of Nodular Cystic Acne. Clin. Exp. Dermatol. 13, 67– 71, DOI: 10.1111/j.1365-2230.1988.tb00659.x
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A comparison of dapsone with 13-cis retinoic acid in the treatment of nodular cystic acne
Prendiville J S; Logan R A; Russell-Jones R
Clinical and experimental dermatology (1988), 13 (2), 67-71 ISSN:0307-6938.
There is no expanded citation for this reference.
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Tan, B. B., Lear, J. T., and Smith, A. G. (1997) Acne Fulminans and Erythema Nodosum during Isotretinoin Therapy Responding to Dapsone. Clin. Exp. Dermatol. 22, 26– 27, DOI: 10.1046/j.1365-2230.1997.1830600.x
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Acne fulminans and erythema nodosum during isotretinoin therapy responding to dapsone
Tan B B; Lear J T; Smith A G
Clinical and experimental dermatology (1997), 22 (1), 26-7 ISSN:0307-6938.
Acne vulgaris is very common, 85% of teenagers being affected at any one time. In most cases, the disease is mild and patients do not present to the dermatologist. Most are instead treated with over-the-counter products and conventional treatment such as peeling agents or topical and systemic antibiotics. Isotretinoin has revolutionized the treatment of severe acne unresponsive to oral antibiotics. Explosive and very severe acne such as pyoderma faciale, acne conglobata and acne fulminans are rare, the features that distinguish acne fulminans from the other conditions being systemic upset with fever, joint pain, malaise and leucocytosis, while there have been two reports of the condition associated with erythema nodosum. The recommended treatment for acne fulminans is a combination of oral steroids and systemic antibiotics, isotretinoin probably not being the treatment of choice. We now report a patient who developed acne fulminans and erythema nodosum within 3 weeks of starting isotretinoin and then responded to dapsone without oral steroids.
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Lopez-Boado, Y. S. and Rubin, B. K. (2008) Macrolides as Immunomodulatory Medications for the Therapy of Chronic Lung Diseases. Curr. Opin. Pharmacol. 8, 286– 291, DOI: 10.1016/j.coph.2008.01.010
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Macrolides as immunomodulatory medications for the therapy of chronic lung diseases
Lopez-Boado, Yolanda S.; Rubin, Bruce K.
Current Opinion in Pharmacology (2008), 8 (3), 286-291CODEN: COPUBK; ISSN:1471-4892. (Elsevier B.V.)
A review. Macrolide antibiotics have potent immunomodulatory activity. The spectrum of action of these antibiotics extends to regulation of leukocyte function and prodn. of inflammatory mediators, control of mucus hypersecretion, resoln. of inflammation, and modulation of host defense mechanisms. Macrolides are now being used or investigated to treat chronic lung inflammatory diseases, including diffuse panbronchiolitis (DPB), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and asthma. Intense research is ongoing to further elucidate the targets and mechanism/s of action of macrolides in eukaryotic cells. In this paper, we review recent findings on novel effects of macrolides on epithelial barrier function and resoln. of inflammation, which may shed light on the mechanisms underlying the beneficial effects of macrolides in the clinic.
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Keicho, N. and Kudoh, S. (2002) Diffuse Panbronchiolitis: Role of Macrolides in Therapy. Am. J. Respir. Med. 1, 119– 131, DOI: 10.1007/BF03256601
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Diffuse panbronchiolitis: role of macrolides in therapy
Keicho, Naoto; Kudoh, Shoji
American Journal of Respiratory Medicine (2002), 1 (2), 119-131CODEN: AJRMAG; ISSN:1175-6365. (Adis International Ltd.)
A review. Diffuse panbronchiolitis (DPB) is characterized by chronic sinobronchial infection and diffuse bilateral micronodular pulmonary lesions consisting of inflammatory cells. Studies on disease etiol. point to a genetic predisposition unique to Asians. Early therapy for DPB was largely symptomatic. The advent of macrolide antibiotics, including erythromycin, roxithromycin and clarithromycin, has strikingly changed disease prognosis. Low-dose, long-term macrolide therapy for DPB originated from detailed observations of response to therapy in a single patient. The bactericidal activity of macrolides, particularly erythromycin, is not a significant factor for their clin. efficacy in DPB. Firstly, irresp. of bacterial clearance, clin. improvement is obsd. in patients treated with erythromycin. Secondly, even in cases with bacterial superinfection with Pseudomonas aeruginosa resistant to macrolides, treatment has proved effective. Thirdly, the recommended dosage of macrolides produces peak levels in tissue that are below the min. inhibitory concns. for major pathogenic bacteria that colonize the airway. In the last two decades, the possible mechanism underlying the effectiveness of macrolide therapy has been extensively studied. The proposed mechanism of action includes inhibition of excessive mucus and water secretion from the airway epithelium, inhibition of neutrophil accumulation in the large airway, inhibition of lymphocyte and macrophage accumulation around the small airway, and modulation of bacterial virulence. The great success of macrolide therapy in diffuse panbronchiolitis may extend its application to the treatment of other chronic inflammatory disorders. If the anti-inflammatory activity of macrolides is independent of their bactericidal effect, new anti-inflammatory macrolides without antimicrobial activity should be developed to minimize emergence of macrolide-resistant micro-organisms.
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Pradhan, S., Madke, B., Kabra, P., and Singh, A. L. (2016) Anti-Inflammatory and Immunomodulatory Effects of Antibiotics and Their Use in Dermatology. Indian J. Dermatol. 61, 469– 481, DOI: 10.4103/0019-5154.190105
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Anti-inflammatory and Immunomodulatory Effects of Antibiotics and Their Use in Dermatology
Pradhan Swetalina; Madke Bhushan; Kabra Poonam; Singh Adarsh Lata
Indian journal of dermatology (2016), 61 (5), 469-81 ISSN:.
Antibiotics (antibacterial, antiviral, and antiparasitic) are class of drugs which result in either killing or inhibiting growth and multiplication of infectious organisms. Antibiotics are commonly prescribed by all specialties for treatment of infections. However, antibiotics have hitherto immunomodulatory and anti-inflammatory properties and can be exploited for various noninfectious dermatoses. Dermatologists routinely prescribe antibiotics in treatment of various noninfectious disorders. This study will review anti-inflammatory and immunomodulatory effects of antibiotics and their use in dermatology.
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Schaeverbeke, T., Lequen, L., de Barbeyrac, B., Labbe, L., Bebear, C. M., Morrier, Y., Bannwarth, B., Bebear, C. M., and Dehais, J. (1998) Propionibacterium Acnes Isolated from Synovial Tissue and Fluid in a Patient with Oligoarthritis Associated with Acne and Pustulosis. Arthritis Rheum. 41, 1889– 1893, DOI: 10.1002/1529-0131(199810)41:10<1889::AID-ART23>3.0.CO;2-F
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Propionibacterium acnes isolated from synovial tissue and fluid in a patient with oligoarthritis associated with acne and pustulosis
Schaeverbeke T; Lequen L; de Barbeyrac B; Labbe L; Bebear C M; Morrier Y; Bannwarth B; Bebear C; Dehais J
Arthritis and rheumatism (1998), 41 (10), 1889-93 ISSN:0004-3591.
This report describes the case of a patient with a 14-month course of severe oligoarthritis associated with acne. Pure cultures of Propionibacterium acnes were isolated from synovial tissue and synovial fluid specimens collected from the same joint after a 4-month interval. After 2 months of treatment with roxithromycin 300 mg/day, rifampicin 1,200 mg/day, and a nonsteroidal antiinflammatory drug (NSAID), followed by 4 months of treatment with azithromycin 1 gm/week and an NSAID, the synovitis persisted. Cultures of skin lesions and synovial fluid at this time were negative. Although P acnes has previously been isolated from bone specimens obtained from patients with osteitis associated with acne, this is the first report of the isolation of this microorganism from the synovial tissue of a patient with arthritis associated with acne. Our findings raise the question of the role of P acnes in the pathogenesis of arthritis associated with acne.
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Nishimuta, K. and Ito, Y. (2003) Effects of Metronidazole and Tinidazole Ointments on Models for Inflammatory Dermatitis in Mice. Arch. Dermatol. Res. 294, 544– 551, DOI: 10.1007/s00403-002-0381-4
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Effects of metronidazole and tinidazole ointments on models for inflammatory dermatitis in mice
Nishimuta, K.; Ito, Y.
Archives of Dermatological Research (2003), 294 (12), 544-551CODEN: ADREDL; ISSN:0340-3696. (Springer-Verlag)
We investigated the effects of 1-4% ointments of metronidazole and tinidazole (derivs. of nitroimidazole) on models of inflammatory dermatitis evoked by antigen, hapten and monoclonal anti-dinitrophenol (DNP) IgE antibody in mice. Metronidazole and tinidazole ointments (1) suppressed the late-phase reaction (LPR) of biphasic ear edema in mice sensitized with ovalbumin (OA), (2) suppressed trinitrochlorobenzene-induced inflammatory dermatitis, (3) suppressed the immediate phase reactions and LPR in mice passively sensitized with anti-DNP IgE mAb, and (4) enhanced vascular permeability and the no. of scratching reactions, presumably due to itching, in passively sensitized mice. These results strongly indicate that metronidazole and tinidazole 1-4% ointments possess antiinflammatory, immunosuppressive and anti-itching effects, and have the potential for clin. use in the treatment of human inflammatory skin diseases including atopic dermatitis in addn. to rosacea and acne vulgaris.
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Mendonca, C. O. and Griffiths, C. E. M. (2006) Clindamycin and Rifampicin Combination Therapy for Hidradenitis Suppurativa. Br. J. Dermatol. 154, 977– 978, DOI: 10.1111/j.1365-2133.2006.07155.x
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Clindamycin and rifampicin combination therapy for hidradenitis suppurativa
Mendonca, C. O.; Griffiths, C. E. M.
British Journal of Dermatology (2006), 154 (5), 977-980CODEN: BJDEAZ; ISSN:0007-0963. (Blackwell Publishing Ltd.)
Background: Hidradenitis suppurativa (HS) is a chronic inflammatory condition affecting apocrine gland-bearing areas of the skin. There is currently no satisfactory treatment. Objectives: To assess the efficacy of a 10-wk course of combination clindamycin 300 mg twice daily and rifampicin 300 mg twice daily in the treatment of HS. Methods: Patients who had received combination therapy with clindamycin and rifampicin for HS at one U.K. Dermatol. Center between the years 1998 and 2003 were identified from pharmacy records. Their records were analyzed retrospectively. Results: Fourteen patients with HS had received treatment with combination therapy. Eight of these patients achieved remission and a further two achieved remission when minocycline was substituted for clindamycin. Four patients were unable to tolerate therapy. Conclusions: This small retrospective study indicates that combination therapy with clindamycin and rifampicin may be effective for HS. However, there is a need for a placebo-controlled trial.
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Mela, M., Mancuso, A., and Burroughs, A. K. (2003) Review Article: Pruritus in Cholestatic and Other Liver Diseases. Aliment. Pharmacol. Ther. 17, 857– 870, DOI: 10.1046/j.1365-2036.2003.01458.x
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Review article: pruritus in cholestatic and other liver diseases
Mela, M.; Mancuso, A.; Burroughs, A. K.
Alimentary Pharmacology and Therapeutics (2003), 17 (7), 857-870CODEN: APTHEN; ISSN:0269-2813. (Blackwell Publishing Ltd.)
A review. Pruritus is often the most troublesome symptom in patients with chronic liver disease, particularly when cholestasis is a prominent feature. The exact pathogenesis is unknown, but empirical treatment such as cholestyramine, based on a liver-based origin of pruritus, has been used for many years. Recently, evidence for a central mechanism for pruritus has been obtained, and opioid antagonists have been tried clin. with some benefit, but their use is not widespread. In addn., the pruritus assocd. with intrahepatic cholestasis of pregnancy can now be alleviated in many cases by ursodeoxycholic acid. As it also improves fetal outcome, this should become 1st-line therapy. This article reviews the pathogenesis and therapy of pruritus, highlighting practical aspects to help patients with seemingly intractable pruritus.
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Sarici, G., Cinar, S., Armutcu, F., Altinyazar, C., Koca, R., and Tekin, N. S. (2010) Oxidative Stress in Acne Vulgaris. J. Eur. Acad. Dermatol. Venereol. 24, 763– 767, DOI: 10.1111/j.1468-3083.2009.03505.x
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Oxidative stress in acne vulgaris
Sarici, G.; Cinar, S.; Armutcu, F.; Altinyazar, C.; Koca, R.; Tekin, N. S.
Journal of the European Academy of Dermatology and Venereology (2010), 24 (7), 763-767CODEN: JEAVEQ; ISSN:0926-9959. (Wiley-Blackwell)
Background: Acne vulgaris is one of the common dermatol. diseases and its pathogenesis is multifactorial. In this study, we aimed to det. the effects of oxidative stress in acne vulgaris. Materials and methods: The study involved 32 patients with acne vulgaris in the patient group and 34 healthy adults in the control group. The parameters of oxidative stress such as catalase (CAT), superoxide dismutase (SOD), xanthine oxidase (XO), nitric oxide (NO) and malondialdehyde (MDA) in the venous blood of patients were measured spectrophotometrically. The values were compared with those of the control group. Results: The serum levels of MDA and XO activity in the patients with acne vulgaris were significantly higher than those of the controls. A significantly lower SOD and CAT activity was found in the patient group than in the control group. Although the patient group had higher serum levels of NO than the control group, the difference was not statistically significant. Conclusion: These results suggest that oxidative damage may play a role in the pathogenesis of acne; therefore, significant alterations may occur in the antioxidant defense system.
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Webster, G. F., Leyden, J. J., McGinley, K. J., and McArthur, W. P. (1982) Suppression of Polymorphonuclear Leukocyte Chemotactic Factor Production in Propionibacterium Acnes by Subminimal Inhibitory Concentrations of Tetracycline, Ampicillin, Minocycline, and Erythromycin. Antimicrob. Agents Chemother. 21, 770– 772, DOI: 10.1128/AAC.21.5.770
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Suppression of polymorphonuclear leukocyte chemotactic factor production in Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocycline, and erythromycin
Webster, G. F.; Leyden, J. J.; McGinley, K. J.; McArthur, W. P.
Antimicrobial Agents and Chemotherapy (1982), 21 (5), 770-2CODEN: AMACCQ; ISSN:0066-4804.
P. acnes Is the cause of inflammation in acne vulgaris and produces potent neutrophil chemoattractants. Different strains of P. acnes that were sensitive or resistant to ampicillin, erythromycin, minocycline, and tetracycline were grown in the presence of subminimal inhibitory concns. of the drugs, and their culture supernatants were assayed for neutrophil chemotactic activity. The presence of subminimal inhibitory concns. of ampicillin failed to affect chemotactic factor prodn. by any of the strains. Subminimal inhibitory concns. of tetracycline, minocycline, and erythromycin all produced decreased neutrophil chemotactic activity in P. acnes culture supernatants. This inhibition of chemotactic activity was most pronounced in strains of P. acnes which were susceptible to the drugs. The addn. of antibiotics at appropriate concns. to control supernatants failed to affect neutrophil migration. Thus, subminimal inhibitory concns. of antibiotics are capable of reducing the inflammatory capacity of P. acnes.
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Skidmore, R., Kovach, R., Walker, C., Thomas, J., Bradshaw, M., Leyden, J., Powala, C., and Ashley, R. (2003) Effects of Subantimicrobial-Dose Doxycycline in the Treatment of Moderate Acne. Arch. Dermatol. 139, 459– 464, DOI: 10.1001/archderm.139.4.459
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Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne
Skidmore, Robert; Kovach, Rodney; Walker, Clay; Thomas, John; Bradshaw, Mark; Leyden, James; Powala, Christopher; Ashley, Robert
Archives of Dermatology (2003), 139 (4), 459-464CODEN: ARDEAC; ISSN:0003-987X. (American Medical Association)
The aim of this study was to det. if treatment with subantimicrobial-dose (SD) doxycycline hyclate (20-mg tablets taken twice daily) improved clin. outcome, had any detectable effect on skin flora, led to overgrowth or colonization of skin by opportunistic pathogens, or resulted in an increase in antibiotic resistance by the surface skin microflora in patients with moderate acne compared with placebo. This was multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. The setting was two university-based clinics. Subjects were adults (N = 51) with moderate facial acne. Patients were randomized to receive SD doxycycline (Periostat; CollaGenex Pharmaceuticals Inc, Newtown, PA) or placebo twice daily for 6 mo. The main efficacy outcomes were changes from baseline in nos. of inflammatory, noninflammatory, and total lesions. Secondary outcome measures were changes from baseline of individual counts of papules, pustules, and nodules and global assessments of clin. improvement by patient and physician. Forty patients completed 6 mo of treatment. At 6 mo, the SD doxycycline group had a significantly greater percent redn. in the no. of comedones (P <.01), inflammatory and noninflammatory lesions combined (P <.01), and total inflammatory lesions (P <.05) than did the placebo group. They also had significantly greater improvement according to the clinician's global assessment (P =.03). There were no significant differences in microbial counts between groups and no evidence of change in antibiotic susceptibility or colonization by potential pathogens. The treatment was well tolerated. Twice-daily SD doxycycline treatment significantly reduced the no. of inflammatory and non-inflammatory lesions in patients with moderate facial acne, was well tolerated, had no detectable antimicrobial effect on the skin flora, and did not result in any increase in the no. of severity of resistant organisms.
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Strahl, H. and Hamoen, L. W. (2010) Membrane Potential Is Important for Bacterial Cell Division. Proc. Natl. Acad. Sci. U. S. A. 107, 12281– 12286, DOI: 10.1073/pnas.1005485107
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Membrane potential is important for bacterial cell division
Strahl, Henrik; Hamoen, Leendert W.
Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (27), 12281-12286, S12281/1-S12281/12CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Many cell division-related proteins are located at specific positions in the bacterial cell, and this organized distribution of proteins requires energy. Here, the authors report that the proton motive force, or more specifically the (trans)membrane potential, is directly involved in protein localization. It emerged that the membrane potential modulates the distribution of several conserved cell division proteins such as MinD, FtsA, and the bacterial cytoskeletal protein MreB. The authors show for MinD that this is based on the membrane potential stimulated binding of its C-terminal amphipathic helix. This function of the membrane potential has implications for how these morphogenetic proteins work and provide an explanation for the effects obsd. with certain antimicrobial compds.
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Strahl, H., Burmann, F., and Hamoen, L. W. (2014) The Actin Homologue MreB Organizes the Bacterial Cell Membrane. Nat. Commun. 5, 3442, DOI: 10.1038/ncomms4442
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The actin homologue MreB organizes the bacterial cell membrane
Strahl Henrik; Burmann Frank; Hamoen Leendert W
Nature communications (2014), 5 (), 3442 ISSN:.
The eukaryotic cortical actin cytoskeleton creates specific lipid domains, including lipid rafts, which determine the distribution of many membrane proteins. Here we show that the bacterial actin homologue MreB displays a comparable activity. MreB forms membrane-associated filaments that coordinate bacterial cell wall synthesis. We noticed that the MreB cytoskeleton influences fluorescent staining of the cytoplasmic membrane. Detailed analyses combining an array of mutants, using specific lipid staining techniques and spectroscopic methods, revealed that MreB filaments create specific membrane regions with increased fluidity (RIFs). Interference with these fluid lipid domains (RIFs) perturbs overall lipid homeostasis and affects membrane protein localization. The influence of MreB on membrane organization and fluidity may explain why the active movement of MreB stimulates membrane protein diffusion. These novel MreB activities add additional complexity to bacterial cell membrane organization and have implications for many membrane-associated processes.
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Wenzel, M., Chiriac, A. I., Otto, A., Zweytick, D., May, C., Schumacher, C., Gust, R., Albada, H. B., Penkova, M., Krämer, U., Erdmann, R., Metzler-Nolte, N., Straus, S. K., Bremer, E., Becher, D., Brötz-Oesterhelt, H., Sahl, H.-G., and Bandow, J. E. (2014) Small Cationic Antimicrobial Peptides Delocalize Peripheral Membrane Proteins. Proc. Natl. Acad. Sci. U. S. A. 111, E1409– 18, DOI: 10.1073/pnas.1319900111
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Small cationic antimicrobial peptides delocalize peripheral membrane proteins
Wenzel, Michaela; Chiriac, Alina Iulia; Otto, Andreas; Zweytick, Dagmar; May, Caroline; Schumacher, Catherine; Gust, Ronald; Albada, H. Bauke; Penkova, Maya; Kraemer, Ute; Erdmann, Ralf; Metzler-Nolte, Nils; Straus, Suzana K.; Bremer, Erhard; Becher, Doerte; Broetz-Oesterhelt, Heike; Sahl, Hans-Georg; Bandow, Julia Elisabeth
Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (14), E1409-E1418CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Short antimicrobial peptides rich in arginine (R) and tryptophan (W) interact with membranes. To learn how this interaction leads to bacterial death, the authors characterized the effects of the minimal pharmacophore RWRWRW-NH2. A ruthenium-substituted deriv. of this peptide localized to the membrane in vivo, and the peptide also integrated readily into mixed phospholipid bilayers that resemble Gram-pos. membranes. Proteome and Western blot analyses showed that integration of the peptide caused delocalization of peripheral membrane proteins essential for respiration and cell-wall biosynthesis, limiting cellular energy and undermining cell-wall integrity. This delocalization phenomenon also was obsd. with the cyclic peptide gramicidin S, indicating the generality of the mechanism. Exogenous glutamate increases tolerance to the peptide, indicating that osmotic destabilization also contributes to antibacterial efficacy. Bacillus subtilis responds to peptide stress by releasing osmoprotective amino acids, in part via mechanosensitive channels. This response is triggered by membrane-targeting bacteriolytic peptides of different structural classes as well as by hypoosmotic conditions.
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Pogliano, J., Pogliano, N., and Silverman, J. A. (2012) Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell Division Proteins. J. Bacteriol. 194, 4494– 4504, DOI: 10.1128/JB.00011-12
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Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins
Pogliano, Joe; Pogliano, Nicolas; Silverman, Jared A.
Journal of Bacteriology (2012), 194 (17), 4494-4504CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
Daptomycin is a lipopeptide antibiotic used clin. for the treatment of certain types of Gram-pos. infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Details of the mechanism of action of daptomycin continue to be elucidated, particularly the question of whether daptomycin acts on the cell membrane, the cell wall, or both. Here, we use fluorescence microscopy to directly visualize the interaction of daptomycin with the model Gram-pos. bacterium Bacillus subtilis. We show that the first observable cellular effects are the formation of membrane distortions (patches of membrane) that precede cell death by more than 30 min. Membrane patches are able to recruit the essential cell division protein DivIVA. Recruitment of DivIVA correlates with membrane defects and changes in cell morphol., suggesting a localized alteration in the activity of enzymes involved in cell wall synthesis that could account for previously described effects of daptomycin on cell wall morphol. and septation. Membrane defects colocalize with fluorescently labeled daptomycin, DivIVA, and fluorescent reporters of peptidoglycan biogenesis (Bocillin FL and BODIPY FL-vancomycin), suggesting that daptomycin plays a direct role in these events. Our results support a mechanism for daptomycin with a primary effect on cell membranes that in turn redirects the localization of proteins involved in cell division and cell wall synthesis, causing dramatic cell wall and membrane defects, which may ultimately lead to a breach in the cell membrane and cell death. These results help resolve the long-standing questions regarding the mechanism of action of this important class of antibiotics.
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Morgera, F., Antcheva, N., Pacor, S., Quaroni, L., Berti, F., Vaccari, L., and Tossi, A. (2008) Structuring and Interactions of Human Beta-Defensins 2 and 3 with Model Membranes. J. Pept. Sci. 14, 518– 523, DOI: 10.1002/psc.981
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Structuring and interactions of human β-defensins 2 and 3 with model membranes
Morgera, Francesca; Antcheva, Nikolinka; Pacor, Sabrina; Quaroni, Luca; Berti, Federico; Vaccari, Lisa; Tossi, Alessandro
Journal of Peptide Science (2008), 14 (4), 518-523CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
β-Defensins play an important role in both innate and adaptive immunity, displaying a direct anti-microbial activity against a wide variety of micro-organisms as well as interesting immuno-modulatory effects on host cells. Interaction with biol. membranes appears to be a central theme in modulating these activities, leading to different consequences such as membrane lysis, translocation into the cytoplasm or transfer to a receptor. We have investigated the structuring of human β-defensins (hBD2 and hBD3) and rationally designed variants, in relation to their interactions with real and model membranes. Biophys. methods, such as CD (CD), transmission or reflection IR and dye release were used to probe their structure/activity in the presence of model membranes, while fluorimetric and flow cytometric assays were used to investigate the effects on prokaryotic cells. Our results indicate that structural features, such as the helical N-terminal domains and oligomerization at the membrane surface, may modulate the efficiency of membrane insertion and selectivity for microbial or host-cell membranes. We propose that both peptides interact with membranes as extended β-sheet platforms that present amphipathic helixes for insertion into the lipid bilayer.
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Sass, V., Schneider, T., Wilmes, M., Körner, C., Tossi, A., Novikova, N., Shamova, O., and Sahl, H. G. (2010) Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci. Infect. Immun. 78, 2793– 2800, DOI: 10.1128/IAI.00688-09
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Human β-defensin 3 inhibits cell wall biosynthesis in staphylococci
Sass, Vera; Schneider, Tanja; Wilmes, Miriam; Koerner, Christian; Tossi, Alessandro; Novikova, Natalia; Shamova, Olga; Sahl, Hans-Georg
Infection and Immunity (2010), 78 (6), 2793-2800CODEN: INFIBR; ISSN:0019-9567. (American Society for Microbiology)
Human β-defensin 3 (hBD3) is a highly charged (+11) cationic host defense peptide, produced by epithelial cells and neutrophils. HBD3 retains antimicrobial activity against a broad range of pathogens, including multiresistant Staphylococcus aureus, even under high-salt conditions. Whereas antimicrobial host defense peptides are assumed to act by permeabilizing cell membranes, the transcriptional response pattern of hBD3-treated staphylococcal cells resembled that of vancomycin-treated cells and suggested that inhibition of cell wall biosynthesis is a major component of the killing process. HBD3-treated cells, inspected by transmission electron microscopy, showed localized protrusions of cytoplasmic contents, and anal. of the intracellular pool of nucleotide-activated cell wall precursors demonstrated accumulation of the final sol. precursor, UDP-MurNAc-pentapeptide. Accumulation is typically induced by antibiotics that inhibit membrane-bound steps of cell wall biosynthesis and also demonstrates that hBD3 does not impair the biosynthetic capacity of cells and does not cause gross leakage of small cytoplasmic compds. In in vitro assays of individual membrane-assocd. cell wall biosynthesis reactions (MraY, MurG, FemX, and penicillin-binding protein 2 [PBP2]), hBD3 inhibited those enzymes which use the bactoprenol-bound cell wall building block lipid II as a substrate; quant. anal. suggested that hBD3 may stoichiometrically bind to lipid II. We report that binding of hBD3 to defined, lipid II-rich sites of cell wall biosynthesis may lead to perturbation of the biosynthesis machinery, resulting in localized lesions in the cell wall as demonstrated by electron microscopy. The lesions may then allow for osmotic rupture of cells when defensins are tested under low-salt conditions.
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Kandaswamy, K., Liew, T. H., Wang, C. Y., Huston-Warren, E., Meyer-Hoffert, U., Hultenby, K., Schröder, J. M., Caparon, M. G., Normark, S., Henriques-Normark, B., Hultgren, S. J., and Kline, K. A. (2013) Focal Targeting by Human β-Defensin 2 Disrupts Localized Virulence Factor Assembly Sites in Enterococcus Faecalis. Proc. Natl. Acad. Sci. U. S. A. 110, 20230– 20235, DOI: 10.1073/pnas.1319066110
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Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis
Kandaswamy, Kumaravel; Liew, Tze Horng; Wang, Charles Y.; Huston-Warren, Emily; Meyer-Hoffert, Ulf; Hultenby, Kjell; Schroder, Jens M.; Caparon, Michael G.; Normark, Staffan; Henriques-Normark, Birgitta; Hultgren, Scott J.; Kline, Kimberly A.
Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (50), 20230-20235,S20230/1-S20230/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Virulence factor secretion and assembly occurs at spatially restricted foci in some Gram-pos. bacteria. Given the essentiality of the general secretion pathway in bacteria and the contribution of virulence factors to disease progression, the foci that coordinate these processes are attractive antimicrobial targets. In this study, the authors show in Enterococcus faecalis that SecA and sortase A, required for the attachment of virulence factors to the cell wall, localize to discrete domains near the septum or nascent septal site as the bacteria proceed through the cell cycle. They also demonstrate that cationic human β-defensins interact with E. faecalis at discrete septal foci, and this exposure disrupts sites of localized secretion and sorting. Modification of anionic lipids by multiple peptide resistance factor, a protein that confers antimicrobial peptide resistance by electrostatic repulsion, renders E. faecalis more resistant to killing by defensins and less susceptible to focal targeting by the cationic antimicrobial peptides. These data suggest a paradigm in which focal targeting by antimicrobial peptides is linked to their killing efficiency and to disruption of virulence factor assembly.
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Kwakman, P. H. S., Krijgsveld, J., de Boer, L., Nguyen, L. T., Boszhard, L., Vreede, J., Dekker, H. L., Speijer, D., Drijfhout, J. W., te Velde, A. A., Crielaard, W., Vogel, H. J., Vandenbroucke-Grauls, C. M. J. E., and Zaat, S. A. J. (2011) Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements. J. Biol. Chem. 286, 43506– 43514, DOI: 10.1074/jbc.M111.248641
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Native thrombocidin-1 and unfolded thrombocidin-1 exert antimicrobial activity via distinct structural elements
Kwakman, Paulus H. S.; Krijgsveld, Jeroen; de Boer, Leonie; Nguyen, Leonard T.; Boszhard, Laura; Vreede, Jocelyne; Dekker, Henk L.; Speijer, Dave; Drijfhout, Jan W.; te Velde, Anje A.; Crielaard, Wim; Vogel, Hans J.; Vandenbroucke-Grauls, Christina M. J. E.; Zaat, Sebastian A. J.
Journal of Biological Chemistry (2011), 286 (50), 43506-43514, S43506/1-S43506/2CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Chemokines (chemotactic cytokines) can have direct antimicrobial activity, which is apparently related to the presence of a distinct pos. charged patch on the surface. However, chemokines can retain antimicrobial activity upon linearization despite the loss of their pos. patch, thus questioning the importance of this patch for activity. Thrombocidin-1 (TC-1) is a microbicidal protein isolated from human blood platelets. TC-1 only differs from the chemokine NAP-2/CXCL7 by a two-amino acid C-terminal deletion, but this truncation is crucial for antimicrobial activity. The authors assessed the structure-activity relationship for antimicrobial activity of TC-1. Redn. of the charge of the TC-1-pos. patch by replacing lysine 17 with alanine reduced the activity against bacteria and almost abolished activity against the yeast Candida albicans. Conversely, augmentation of the pos. patch by increasing charge d. or size resulted in a 2-3-fold increased activity against Staphylococcus aureus, Escherichia coli, and Bacillus subtilis but did not substantially affect activity against C. albicans. Redn. of TC-1 resulted in loss of the folded conformation, but this disruption of the pos. patch did not affect antimicrobial activity. Using overlapping 15-mer synthetic peptides, we demonstrate peptides corresponding to the N-terminal part of TC-1 to have similar antimicrobial activity as intact TC-1. Although we demonstrate that the pos. patch is essential for activity of folded TC-1, unfolded TC-1 retained antimicrobial activity despite the absence of a pos. patch. This activity is probably exerted by a linear peptide stretch in the N-terminal part of the mol. It is concluded that intact TC-1 and unfolded TC-1 exert antimicrobial activity via distinct structural elements.
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Omardien, S., Drijfhout, J. W., Vaz, F. M., Wenzel, M., Hamoen, L. W., Zaat, S. A. J., and Brul, S. (2018) Bactericidal Activity of Amphipathic Cationic Antimicrobial Peptides Involves Altering the Membrane Fluidity When Interacting with the Phospholipid Bilayer. Biochim. Biophys. Acta, Biomembr. 1860, 2404, DOI: 10.1016/j.bbamem.2018.06.004
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Bactericidal activity of amphipathic cationic antimicrobial peptides involves altering the membrane fluidity when interacting with the phospholipid bilayer
Omardien, Soraya; Drijfhout, Jan W.; Vaz, Frederic M.; Wenzel, Michaela; Hamoen, Leendert W.; Zaat, Sebastian A. J.; Brul, Stanley
Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (11), 2404-2415CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Amphipathic cationic antimicrobial peptides (AMPs) TC19 and TC84, derived from the major AMPs of human blood platelets, thrombocidins, and Bactericidal Peptide 2 (BP2), a synthetic designer peptide showed to perturb the membrane of Bacillus subtilis. We aimed to det. the means by which the three AMPs cause membrane perturbation in vivo using B. subtilis and to evaluate whether the membrane alterations are dependent on the phospholipid compn. of the membrane. Physiol. anal. was employed using Alexa Fluor 488 labeled TC84, various fluorescence dyes, fluorescent microscopy techniques and structured illumination microscopy. TC19, TC84 and BP2 created extensive fluidity domains in the membrane that are permeable, thus facilitating the entering of the peptides and the leakage of the cytosol. The direct interaction of the peptides with the bilayer create the fluid domains. The changes caused in the packing of the phospholipids lead to the delocalization of membrane bound proteins, thus contributing to the cell's destruction. The changes made to the membrane appeared to be not dependent on the compn. of the phospholipid bilayer. The distortion caused to the fluidity of the membrane by the AMPs is sufficient to facilitate the entering of the peptides and leakage of the cytosol. Here we show in vivo that cationic AMPs cause "membrane leaks" at the site of membrane insertion by altering the organization and fluidity of the membrane. Our findings thus contribute to the understanding of the membrane perturbation characteristic of cationic AMPs.
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Omardien, S., Drijfhout, J. W., van Veen, H., Schachtschabel, S., Riool, M., Hamoen, L. W., Brul, S., and Zaat, S. A. J. (2018) Synthetic Antimicrobial Peptides Delocalize Membrane Bound Proteins Thereby Inducing a Cell Envelope Stress Response. Biochim. Biophys. Acta, Biomembr. 1860, 2416– 2427, DOI: 10.1016/j.bbamem.2018.06.005
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Synthetic antimicrobial peptides delocalize membrane bound proteins thereby inducing a cell envelope stress response
Omardien, Soraya; Drijfhout, Jan W.; van Veen, Henk; Schachtschabel, Soraya; Riool, Martijn; Hamoen, Leendert W.; Brul, Stanley; Zaat, Sebastian A. J.
Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (11), 2416-2427CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Three amphipathic cationic antimicrobial peptides (AMPs) were characterized by detg. their effect on Gram-pos. bacteria using Bacillus subtilis strain 168 as a model organism. These peptides were TC19 and TC84, derivs. of thrombocidin-1 (TC-1), the major AMPs of human blood platelets, and Bactericidal Peptide 2 (BP2), a synthetic designer peptide based on human bactericidal permeability increasing protein (BPI). To elucidate the possible mode of action of the AMPs we performed a transcriptomic anal. using microarrays. Physiol. analyses were performed using transmission electron microscopy (TEM), fluorescence microscopy and various B. subtilis mutants that produce essential membrane bound proteins fused to green fluorescent protein (GFP). The transcriptome anal. showed that the AMPs induced a cell envelope stress response (cell membrane and cell wall). The cell membrane stress response was confirmed with the physiol. observations that TC19, TC84 and BP2 perturb the membrane of B. subtilis. Using B. subtilis mutants, we established that the cell wall stress response is due to the delocalization of essential membrane bound proteins involved in cell wall synthesis. Other essential membrane proteins, involved in cell membrane synthesis and metab., were also delocalized due to alterations caused by the AMPs. We showed that peptides TC19, TC84 and BP2 perturb the membrane causing essential proteins to delocalize, thus preventing the possible repair of the cell envelope after the initial interference with the membrane. These AMPs show potential for eventual clin. application against Gram-pos. bacterial cells and merit further application-oriented investigation.
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Omardien, S., Drijfhout, J. W., Zaat, S. A., and Brul, S. (2018) Cationic Amphipathic Antimicrobial Peptides Perturb the Inner Membrane of Germinated Spores Thus Inhibiting Their Outgrowth. Front. Microbiol. 9, 2277, DOI: 10.3389/fmicb.2018.02277
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Cationic Amphipathic Antimicrobial Peptides Perturb the Inner Membrane of Germinated Spores Thus Inhibiting Their Outgrowth
Omardien Soraya; Brul Stanley; Drijfhout Jan Wouter; Zaat Sebastian A
Frontiers in microbiology (2018), 9 (), 2277 ISSN:1664-302X.
The mode of action of four cationic amphipathic antimicrobial peptides (AMPs) was evaluated against the non-pathogenic, Gram-positive, spore-forming bacterium, Bacillus subtilis. The AMPs were TC19, TC84, BP2, and the lantibiotic Nisin A. TC19 and TC84 were derived from the human thrombocidin-1. Bactericidal peptide 2 (BP2) was derived from the human bactericidal permeability increasing protein (BPI). We employed structured illumination microscopy (SIM), fluorescence microscopy, Alexa 488-labeled TC84, B. subtilis mutants producing proteins fused to the green fluorescent protein (GFP) and single-cell live imaging to determine the effects of the peptides against spores. TC19, TC84, BP2, and Nisin A showed to be bactericidal against germinated spores by perturbing the inner membrane, thus preventing outgrowth to vegetative cells. Single cell live imaging showed that the AMPs do not affect the germination process, but the burst time and subsequent generation time of vegetative cells. Alexa 488-labeled TC84 suggested that the TC84 might be binding to the dormant spore-coat. Therefore, dormant spores were also pre-coated with the AMPs and cultured on AMP-free culture medium during single-cell live imaging. Pre-coating of the spores with TC19, TC84, and BP2 had no effect on the germination process, and variably affected the burst time and generation time. However, the percentage of spores that burst and grew out into vegetative cells was drastically lower when pre-coated with Nisin A, suggesting a novel application potential of this lantibiotic peptide against spores. Our findings contribute to the understanding of AMPs and show the potential of AMPs as eventual therapeutic agents against spore-forming bacteria.
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Gray, D. A. and Wenzel, M. (2020) More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin. Antibiotics (Basel, Switz.) 9, 17, DOI: 10.3390/antibiotics9010017
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More than a pore: a current perspective on the in vivo mode of action of the lipopeptide antibiotic daptomycin
Gray, Declan Alan; Wenzel, Michaela
Antibiotics (Basel, Switzerland) (2020), 9 (1), 17CODEN: ABSNC4; ISSN:2079-6382. (MDPI AG)
Daptomycin is a cyclic lipopeptide antibiotic, which was discovered in 1987 and entered the market in 2003. To date, it serves as last resort antibiotic to treat complicated skin infections, bacteremia, and right-sided endocarditis caused by Gram-pos. pathogens, most prominently methicillin-resistant Staphylococcus aureus. Daptomycin was the last representative of a novel antibiotic class that was introduced to the clinic. It is also one of the few membrane-active compds. that can be applied systemically. While membrane-active antibiotics have long been limited to topical applications and were generally excluded from systemic drug development, they promise slower resistance development than many classical drugs that target single proteins. The success of daptomycin together with the emergence of more and more multi-resistant superbugs attracted renewed interest in this compd. class. Studying daptomycin as a pioneering systemic membrane-active compd. might help to pave the way for future membrane-targeting antibiotics. However, more than 30 years after its discovery, the exact mechanism of action of daptomycin is still debated. In particular, there is a prominent discrepancy between in vivo and in vitro studies. In this review, we discuss the current knowledge on the mechanism of daptomycin against Gram-pos. bacteria and try to offer explanations for these conflicting observations.
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Scheinpflug, K., Wenzel, M., Krylova, O., Bandow, E. J., Dathe, M., and Strahl, H. (2017) Antimicrobial Peptide CWFW Kills by Combining Lipid Phase Separation with Autolysis. Sci. Rep. 7, 44332, DOI: 10.1038/srep44332
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Antimicrobial peptide cWFW kills by combining lipid phase separation with autolysis
Scheinpflug Kathi; Krylova Oxana; Dathe Margitta; Wenzel Michaela; Bandow Julia E; Strahl Henrik
Scientific reports (2017), 7 (), 44332 ISSN:.
The synthetic cyclic hexapeptide cWFW (cyclo(RRRWFW)) has a rapid bactericidal activity against both Gram-positive and Gram-negative bacteria. Its detailed mode of action has, however, remained elusive. In contrast to most antimicrobial peptides, cWFW neither permeabilizes the membrane nor translocates to the cytoplasm. Using a combination of proteome analysis, fluorescence microscopy, and membrane analysis we show that cWFW instead triggers a rapid reduction of membrane fluidity both in live Bacillus subtilis cells and in model membranes. This immediate activity is accompanied by formation of distinct membrane domains which differ in local membrane fluidity, and which severely disrupts membrane protein organisation by segregating peripheral and integral proteins into domains of different rigidity. These major membrane disturbances cause specific inhibition of cell wall synthesis, and trigger autolysis. This novel antibacterial mode of action holds a low risk to induce bacterial resistance, and provides valuable information for the design of new synthetic antimicrobial peptides.
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Saeloh, D., Tipmanee, V., Jim, K. K., Dekker, M. P., Bitter, W., Voravuthikunchai, S. P., Wenzel, M., and Hamoen, L. W. (2018) The Novel Antibiotic Rhodomyrtone Traps Membrane Proteins in Vesicles with Increased Fluidity. PLoS Pathog. 14, e1006876 DOI: 10.1371/journal.ppat.1006876
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The novel antibiotic rhodomyrtone traps membrane proteins in vesicles with increased fluidity
Saeloh, Dennapa; Tipmanee, Varomyalin; Jim, Kin Ki; Dekker, Marien P.; Bitter, Wilbert; Voravuthikunchai, Supayang P.; Wenzel, Michaela; Hamoen, Leendert W.
PLoS Pathogens (2018), 14 (2), e1006876/1-e1006876/35CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
The acylphloroglucinol rhodomyrtone is a promising new antibiotic isolated from the rose myrtle Rhodomyrtus tomentosa, a plant used in Asian traditional medicine. While many studies have demonstrated its antibacterial potential in a variety of clin. applications, very little is known about the mechanism of action of rhodomyrtone. Preceding studies have been focused on intracellular targets, but no specific intracellular protein could be confirmed as main target. Using live cell, high-resoln., and electron microscopy we demonstrate that rhodomyrtone causes large membrane invaginations with a dramatic increase in fluidity, which attract a broad range of membrane proteins. Invaginations then form intracellular vesicles, thereby trapping these proteins. Aberrant protein localization impairs several cellular functions, including the respiratory chain and the ATP synthase complex. Being uncharged and devoid of a particular amphipathic structure, rhodomyrtone did not seem to be a typical membrane-inserting mol. In fact, mol. dynamics simulations showed that instead of inserting into the bilayer, rhodomyrtone transiently binds to phospholipid head groups and causes distortion of lipid packing, providing explanations for membrane fluidization and induction of membrane curvature. Both its transient binding mode and its ability to form protein- trapping membrane vesicles are unique, making it an attractive new antibiotic candidate with a novel mechanism of action.
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Zhanel, G. G., Schweizer, F., and Karlowsky, J. A. (2012) Oritavancin: Mechanism of Action. Clin. Infect. Dis. 54, S214– S219, DOI: 10.1093/cid/cir920
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Oritavancin: Mechanism of Action
Zhanel, George G.; Schweizer, Frank; Karlowsky, James A.
Clinical Infectious Diseases (2012), 54 (Suppl. 3), S214-S219CODEN: CIDIEL; ISSN:1058-4838. (Oxford University Press)
A review. Oritavancin is a semisynthetic lipoglycopeptide analog of vancomycin that contains the heptapeptide core common to all glycopeptides. It differs from vancomycin by the presence of a hydrophobic N-4-(4-chlorophenyl)benzyl (also referred to as 4'-chlorobiphenylmethyl) substituent on the disaccharide sugar, the addn. of a 4-epi-vancosamine monosaccharide to the amino acid residue in ring 6, and the replacement of the vancosamine moiety by 4-epi-vancosamine. One mechanism of action of oritavancin is inhibition of transglycosylation (important in peptidoglycan synthesis) by binding to -alanyl-alanine stem termini in Gram-pos. bacteria. The inhibition of peptidoglycan synthesis via inhibition of transglycosylation is common to all glycopeptides (vancomycin) and lipoglycopeptides. Secondary binding of oritavancin to the pentaglycyl (Asp/Asn) bridging segment in peptidoglycan also occurs, which distinguishes it from vancomycin and contributes to oritavancin's activity vs. vancomycin-resistant organisms. The presence of the hydrophobic 4'-chlorobiphenylmethyl group allows for interaction and disruption of the cell membrane, resulting in depolarization, permeabilization, and concn.-dependent, rapid cell death. This mechanism is shared with telavancin but not vancomycin and results in activity against daptomycin-nonsusceptible organisms. In conclusion, oritavancin's mechanism of action involves at least 3 known mechanisms: inhibition of transglycosylation, inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin's multiple mechanisms of action confer activity against vancomycin-susceptible and -resistant organisms, as well as rapid, concn.-dependent killing vs. actively growing, stationary phase, and biofilm-producing Gram-pos. bacteria.
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Higgins, D. L., Chang, R., Debabov, D. V., Leung, J., Wu, T., Krause, K. M., Sandvik, E., Hubbard, J. M., Kaniga, K., Schmidt, D. E., Gao, Q., Cass, R. T., Karr, D. E., Benton, B. M., and Humphrey, P. P. (2005) Telavancin, a Multifunctional Lipoglycopeptide, Disrupts Both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistan Staphylococcus Aureus. Antimicrob. Agents Chemother. 49, 1127– 1134, DOI: 10.1128/AAC.49.3.1127-1134.2005
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Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus
Higgins, Deborah L.; Chang, Ray; Debabov, Dmitri V.; Leung, Joey; Wu, Terry; Krause, Kevin M.; Sandvik, Erik; Hubbard, Jeffrey M.; Kaniga, Kone; Schmidt, Donald E., Jr.; Gao, Qiufeng; Cass, Robert T.; Karr, Dane E.; Benton, Bret M.; Humphrey, Patrick P.
Antimicrobial Agents and Chemotherapy (2005), 49 (3), 1127-1134CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
The emergence and spread of multidrug-resistant Gram-pos. bacteria represent a serious clin. problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clin. relevant Gram-pos. pathogens. Here, the authors demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As obsd. with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concn.-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K+. The timing of these changes correlated with rapid, concn.-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were obsd. with the bacterial cell wall and cell membrane relative to vancomycin. It is suggested that this multifunctional mechanism of action confers advantageous antibacterial properties.
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Corti, A. and Cassani, G. (1985) Synthesis and Characterization of D-Alanyl-D-Alanine-Agarose. Appl. Biochem. Biotechnol. 11, 101– 109, DOI: 10.1007/BF02798542
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Synthesis and characterization of D-alanyl-D-alanine-agarose. A new bioselective adsorbent for affinity chromatography of glycopeptide antibiotics
Corti, Angelo; Cassani, Giovanni
Applied Biochemistry and Biotechnology (1985), 11 (2), 101-9CODEN: ABIBDL; ISSN:0273-2289.
A new affinity absorbent, using D-alanyl-D-alanine [923-16-0] as ligand, has been prepd. The dipeptide immobilized on Activated CH-Sepharose 4B [D-Ala-D-Ala-agarose (I) [95077-98-8]] bioselectively binds the glycopeptide antibiotics teicoplanin [61036-62-2], vancomycin [1404-90-6], ristocetin A [11021-66-2] (vancomycin-like group of antibiotics) while it does not bind other antibiotics equally active on cell wall biosynthesis but with target sites other than D-ala-D-ala. Teicoplanin, vancomycin, and ristocetin A have similar binding characteristics for the immobilized dipeptide, as indicated by equil. binding expts. The affinity consts. of the 3 antibiotics for I is of the same order of magnitude (105 L mol-1) and the no. of effective binding sites is similar for each antibiotic (6-7 μEq/mL gel). The adsorption is biospecific as no binding has been obsd. to immobilized L-alanyl-L-alanine. I was successfully used to purify teicoplanin from mixts. of different complexity and for concomitant extn. and purifn. from fermn. liquors by both batch adsorption and column chromatog. The antibiotic can be recovered from the resin in high yields by elution at pH 11.
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Cheng, M., Ziora, Z. M., Hansford, K. A., Blaskovich, M. A., Butler, M. S., and Cooper, M. A. (2014) Anti-Cooperative Ligand Binding and Dimerisation in the Glycopeptide Antibiotic Dalbavancin. Org. Biomol. Chem. 12, 2568– 2575, DOI: 10.1039/C3OB42428F
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Anti-cooperative ligand binding and dimerisation in the glycopeptide antibiotic dalbavancin
Cheng, Mu; Ziora, Zyta M.; Hansford, Karl A.; Blaskovich, Mark A.; Butler, Mark S.; Cooper, Matthew A.
Organic & Biomolecular Chemistry (2014), 12 (16), 2568-2575CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
Dalbavancin, a semi-synthetic glycopeptide with enhanced antibiotic activity compared to vancomycin and teicoplanin, binds to the C-terminal lysyl-D-alanyl-D-alanine subunit of Lipid II, inhibiting peptidoglycan biosynthesis. In this study, micro-calorimetry (ITC) and electrospray ionization (ESI)-MS have been used to investigate the relationship between oligomerization of dalbavancin and binding of a Lipid II peptide mimic, diacetyl-Lys-D-Ala-D-Ala (Ac2-Kaa). Dalbavancin dimerized strongly in an anti-cooperative manner with ligand-binding, as was the case for ristocetin A, but not for vancomycin and teicoplanin. Dalbavancin and ristocetin A both adopt an 'closed' conformation upon ligand binding, suggesting anti-cooperative dimerization with ligand-binding may be a general feature of dalbavancin/ristocetin A-like glycopeptides. Understanding these effects may provide insight into design of novel dalbavancin derivs. with cooperative ligand-binding and dimerization characteristics that could enhance antibiotic activity.
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Wenzel, M., Kohl, B., Münch, D., Raatschen, N., Albada, H. B., Hamoen, L., Metzler-Nolte, N., Sahl, H. G., and Bandow, J. E. (2012) Proteomic Response of Bacillus Subtilis to Lantibiotics Reflects Differences in Interaction with the Cytoplasmic Membrane. Antimicrob. Agents Chemother. 56, 5749– 5757, DOI: 10.1128/AAC.01380-12
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Proteomic response of Bacillus subtilis to lantibiotics reflects differences in interaction with the cytoplasmic membrane
Wenzel, Michaela; Kohl, Bastian; Muench, Daniela; Raatschen, Nadja; Albada, H. Bauke; Hamoen, Leendert; Metzler-Nolte, Nils; Sahl, Hans-Georg; Bandow, Julia E.
Antimicrobial Agents and Chemotherapy (2012), 56 (11), 5749-5757CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
Mersacidin, gallidermin, and nisin are lantibiotics, antimicrobial peptides contg. lanthionine. They show potent antibacterial activity. All three interfere with cell wall biosynthesis by binding lipid II, but they display different levels of interaction with the cytoplasmic membrane. On one end of the spectrum, mersacidin interferes with cell wall biosynthesis by binding lipid II without integrating into bacterial membranes. On the other end of the spectrum, nisin readily integrates into membranes, where it forms large pores. It destroys the membrane potential and causes leakage of nutrients and ions. Gallidermin, in an intermediate position, also readily integrates into membranes. However, pore formation occurs only in some bacteria and depends on membrane compn. The authors studied the impact of nisin, gallidermin, and mersacidin on cell wall integrity, membrane pore formation, and membrane depolarization in Bacillus subtilis. The impact of the lantibiotics on the cell envelope was correlated to the proteomic response they elicit in B. subtilis. By drawing on a proteomic response library, including other envelope-targeting antibiotics such as bacitracin, vancomycin, gramicidin S, or valinomycin, YtrE could be identified as the most reliable marker protein for interfering with membrane-bound steps of cell wall biosynthesis. NadE and PspA were identified as markers for antibiotics interacting with the cytoplasmic membrane.
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Bonelli, R. R., Schneider, T., Sahl, H.-G., and Wiedemann, I. (2006) Insights into in Vivo Activities of Lantibiotics from Gallidermin and Epidermin Mode-of-Action Studies. Antimicrob. Agents Chemother. 50, 1449– 1457, DOI: 10.1128/AAC.50.4.1449-1457.2006
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Insights into in vivo activities of lantibiotics from gallidermin and epidermin mode-of-action studies
Bonelli, Raquel Regina; Schneider, Tanja; Sahl, Hans-Georg; Wiedemann, Imke
Antimicrobial Agents and Chemotherapy (2006), 50 (4), 1449-1457CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
The activity of lanthionine-contg. peptide antibiotics (lantibiotics) is based on different killing mechanisms which may be combined in one mol. The prototype lantibiotic nisin inhibits peptidoglycan synthesis and forms pores through specific interaction with the cell wall precursor lipid II. Gallidermin and epidermin possess the same putative lipid II binding motif as nisin; however, both peptides are considerably shorter (22 amino acids, compared to 34 in nisin). We demonstrate that in model membranes, lipid II-mediated pore formation by gallidermin depends on membrane thickness. With intact cells, pore formation was less pronounced than for nisin and occurred only in some strains. In Lactococcus lactis subsp. cremoris HP, gallidermin was not able to release K+, and a mutant peptide, [A12L]gallidermin, in which the ability to form pores was disrupted, was as potent as wild-type gallidermin, indicating that pore formation does not contribute to killing. In contrast, nisin rapidly formed pores in the L. lactis strain; however, it was approx. 10-fold less effective in killing. The superior activity of gallidermin in a cell wall biosynthesis assay may help to explain this high potency. Generally, it appears that the multiple activities of lantibiotics combine differently for individual target strains.
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Brötz, H., Bierbaum, G., Leopold, K., Reynolds, P. E., and Sahl, H. G. (1998) The Lantibiotic Mersacidin Inhibits Peptidoglycan Synthesis by Targeting Lipid II. Antimicrob. Agents Chemother. 42, 154– 160, DOI: 10.1128/AAC.42.1.154
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The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting lipid II
Brotz, Heike; Bierbaum, Gabriele; Leopold, Klaus; Reynolds, Peter E.; Sahl, Hans-Georg
Antimicrobial Agents and Chemotherapy (1998), 42 (1), 154-160CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
The lantibiotic mersacidin exerts its bactericidal action by inhibition of peptidoglycan biosynthesis. It interferes with the membrane-assocd. transglycosylation reaction; during this step the ultimate monomeric peptidoglycan precursor, undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-GlcNAc (lipid II) is converted into polymeric nascent peptidoglycan. In the present study we demonstrate that the mol. basis of this inhibition is the interaction of mersacidin with lipid II. The adsorption of [14C]mersacidin to growing cells, as well as to isolated membranes capable of in vitro peptidoglycan synthesis, was strictly dependent on the availability of lipid II, and antibiotic inhibitors of lipid II formation strongly interfered with this binding. Direct evidence for the interaction was provided by studies with isolated lipid II. [14C]mersacidin assocd. tightly with [14C]lipid II micelles; the complex was stable even in the presence of 1% sodium dodecyl sulfate. Furthermore, the addn. of isolated lipid II to the culture broth efficiently antagonized the bactericidal activity of mersacidin. In contrast to the glycopeptide antibiotics, complex formation does not involve the C-terminal D-alanyl-D-alanine moiety of the lipid intermediate. Thus, the interaction of mersacidin with lipid II apparently occurs via a binding site which is not targeted by any antibiotic currently in use.
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Paris, J.-B., Seyer, D., Jouenne, T., and Thébault, P. (2017) Elaboration of Antibacterial Plastic Surfaces by a Combination of Antiadhesive and Biocidal Coatings of Natural Products. Colloids Surf., B 156, 186– 193, DOI: 10.1016/j.colsurfb.2017.05.025
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Elaboration of antibacterial plastic surfaces by a combination of antiadhesive and biocidal coatings of natural products
Paris, Jean-Baptiste; Seyer, Damien; Jouenne, Thierry; Thebault, Pascal
Colloids and Surfaces, B: Biointerfaces (2017), 156 (), 186-193CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
Antibacterial polyolefins surfaces, combining biocidal and antiadhesive properties, were elaborated by a covalent grafting of antimicrobial peptides (AMPs), able to kill adherent bacteria, on a pre-immobilized hyaluronic acid (HA) layer, able to repel the micro-organisms. Different HA activation rate for its immobilization, were used to change HA layer morphol. and no. of residual free carboxylic acid functions for AMPs grafting. Based on adhesion tests on Staphylococcus epidermidis and microscopy fluorescent observations, the presence of the two combined properties was shown to be depended on the HA activation rate. Thus, the best addn. effect was obsd. for an AMP grafting on a surface based on a high HA activation, data pointing out a decrease of the bacterial adhesion up to 99.8% and a perturbation of the bacterial membrane integrity of adhered bacteria. On the contrary, a decrease of the antibacterial activity was obsd. for an AMP grafting on a surface based on a low HA activation.
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Ulm, H. and Schneider, T. (2016) Targeting Bactoprenol-Coupled Cell Envelope Precursors. Appl. Microbiol. Biotechnol. 100, 7815– 7825, DOI: 10.1007/s00253-016-7732-0
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Targeting bactoprenol-coupled cell envelope precursors
Ulm, Hannah; Schneider, Tanja
Applied Microbiology and Biotechnology (2016), 100 (18), 7815-7825CODEN: AMBIDG; ISSN:0175-7598. (Springer)
A review. Targeting the bactoprenol-coupled cell wall precursor lipid II is a validated antibacterial strategy. In this review, selected prototype lipid II-binding antibiotics of different chem. classes are discussed. Although these compds. attack the same mol. target, they trigger nuanced and diverse cellular effects. Consequently, the mechanisms of antibacterial resistance and the likelihood of resistance development may vary substantially.
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Weidenmaier, C. and Peschel, A. (2008) Teichoic Acids and Related Cell-Wall Glycopolymers in Gram-Positive Physiology and Host Interactions. Nat. Rev. Microbiol. 6, 276– 287, DOI: 10.1038/nrmicro1861
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Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions
Weidenmaier, Christopher; Peschel, Andreas
Nature Reviews Microbiology (2008), 6 (4), 276-287CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
A review. Most Gram-pos. bacteria incorporate membrane- or peptidoglycan-attached carbohydrate-based polymers into their cell envelopes. Such cell-wall glycopolymers (CWGs) often have highly variable structures and have crucial roles in protecting, connecting and controlling the major envelope constituents. Further important roles of CWGs in host-cell adhesion, inflammation and immune activation have also been described in recent years. Identifying and harnessing highly conserved or species-specific structural features of CWGs offers excellent opportunities for developing new antibiotics, vaccines and diagnostics for use in the fight against severe infectious diseases, such as sepsis, pneumonia, anthrax and tuberculosis.
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Kepplinger, B., Morton-Laing, S., Seistrup, K. H., Marrs, E. C. L., Hopkins, A. P., Perry, J. D., Strahl, H., Hall, M. J., Errington, J., and Allenby, N. E. E. (2018) Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin. ACS Chem. Biol. 13, 207– 214, DOI: 10.1021/acschembio.7b00733
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Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin
Kepplinger, Bernhard; Morton-Laing, Stephanie; Seistrup, Kenneth Holst; Marrs, Emma Claire Louise; Hopkins, Adam Paul; Perry, John David; Strahl, Henrik; Hall, Michael John; Errington, Jeff; Ellis Allenby, Nicholas Edward
ACS Chemical Biology (2018), 13 (1), 207-214CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
Antibiotics that interfere with the bacterial cytoplasmic membrane have long term potential for the treatment of infectious diseases, as this mode of action is anticipated to result in low resistance frequency. Vancoresmycin is an understudied natural product antibiotic consisting of a terminal tetramic acid moiety fused to a linear, highly oxygenated, stereochem. complex polyketide chain. Vancoresmycin shows min. inhibitory concns. (MICs) from 0.125 to 2 μg/mL against a range of clin. relevant, antibiotic-resistant Gram-pos. bacteria. Through a comprehensive mode-of-action study, utilizing Bacillus subtilis reporter strains, DiSC3(5) depolarization assays and fluorescence microscopy, we have shown that vancoresmycin selectively targets the cytoplasmic membrane of Gram-pos. bacteria via a non-pore forming, concn.-dependent depolarization mechanism. Whole genome sequencing of the producing strain allowed identification of the 141 kbp gene cluster encoding for vancoresmycin biosynthesis and a preliminary model for its biosynthesis. The size and complex structure of vancoresmycin could confound attempts to generate synthetic analogs. To overcome this problem and facilitate future studies, we identified, cloned and expressed the 141 kbp biosynthetic gene cluster in Streptomyces coelicolor M1152. Elucidation of the mode-of-action of vancoresmycin, together with the heterologous expression system will greatly facilitate further studies of this and related mols.
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Wenzel, M., Patra, M., Senges, C. H. R., Ott, I., Stepanek, J. J., Pinto, A., Prochnow, P., Vuong, C., Langklotz, S., Metzler-Nolte, N., and Bandow, J. E. (2013) Analysis of the Mechanism of Action of Potent Antibacterial Hetero-Tri-Organometallic Compounds: A Structurally New Class of Antibiotics. ACS Chem. Biol. 8, 1442– 1450, DOI: 10.1021/cb4000844
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Analysis of the Mechanism of Action of Potent Antibacterial Hetero-tri-organometallic Compounds: A Structurally New Class of Antibiotics
Wenzel, Michaela; Patra, Malay; Senges, Christoph Helmut Rudi; Ott, Ingo; Stepanek, Jennifer Janina; Pinto, Antonio; Prochnow, Pascal; Vuong, Cuong; Langklotz, Sina; Metzler-Nolte, Nils; Bandow, Julia Elisabeth
ACS Chemical Biology (2013), 8 (7), 1442-1450CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
Two hetero-tri-organometallic compds. with potent activity against Gram-pos. bacteria including multi-resistant Staphylococcus aureus (MRSA) were identified. The compds. consist of a peptide nucleic acid backbone with an alkyne side chain, substituted with a cymantrene, a (dipicolyl)Re(CO)3 moiety, and either a ferrocene (FcPNA) or a ruthenocene (RcPNA). Comparative proteomic anal. indicates the bacterial membrane as antibiotic target structure. FcPNA accumulation in the membrane was confirmed by manganese tracing with at. absorption spectroscopy. Both organometallics disturbed several essential cellular processes taking place at the membrane such as respiration and cell wall biosynthesis, suggesting that the compds. affect membrane architecture. Correlating with enhanced antibacterial activity, oxidative stress was induced only by the ferrocene-substituted compd. The organometallics described here target the cytoplasmic membrane, a clin. proven antibacterial target structure, feature a bactericidal but non-bacteriolytic mode of action and limited cytotoxicity within the limits of soly. Thus, FcPNA represents a promising lead structure for the development of a new synthetic class of antibiotics.
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Andrés, M. T. and Fierro, J. F. (2010) Antimicrobial Mechanism of Action of Transferrins: Selective Inhibition of H⁺-ATPase. Antimicrob. Agents Chemother. 54, 4335– 4342, DOI: 10.1128/AAC.01620-09
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Antimicrobial mechanism of action of transferrins: Selective inhibition of H+-ATPase
Andres, Maria T.; Fierro, Jose F.
Antimicrobial Agents and Chemotherapy (2010), 54 (10), 4335-4342CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
Two bacterial species with different metabolic features, namely, Pseudomonas aeruginosa and Lactococcus lactis, were used as a comparative exptl. model to investigate the antimicrobial target and mechanism of transferrins. In anaerobiosis, P. aeruginosa cells were not susceptible to lactoferrin (hLf) or transferrin (hTf). In aerobiosis, the cells were susceptible but O2 consumption was not modified, indicating that components of the electron transport chain (ETC) were not targeted. However, the respiratory chain inhibitor piericidin A significantly reduced the killing activity of both proteins. Moreover, 2,6-dichlorophenolindophenol (DCIP), a reducing agent that accepts electrons from the ETC coupled to H+ extrusion, made P. aeruginosa susceptible to hLf and hTf in anaerobiosis. These results indicated that active cooperation of the cell was indispensable for the antimicrobial effect. For L. lactis cells lacking an ETC, the absence of a detectable transmembrane elec. potential in hLf-treated cells suggested a loss of H+-ATPase activity. Furthermore, the inhibition of ATPase activity and H+ translocation (inverted membrane vesicles) provided direct evidence of the ability of hLf to inhibit H+-ATPase in L. lactis. The authors propose that hLf and hTf also inhibit the H+-ATPase of respiring P. aeruginosa cells. Such inhibition thereby interferes with reentry of H+ from the periplasmic space to the cytoplasm, resulting in perturbation of intracellular pH and the transmembrane proton gradient. Consistent with this hypothesis, periplasmic H+ accumulation was prevented by anaerobiosis or by piericidin A or was induced by DCIP in anaerobiosis. These results indicate that transferrins target H+-ATPase and interfere with H+ translocation, yielding a lethal effect in vitro.
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Azarkina, N. and Konstantinov, A. A. (2002) Stimulation of Menaquinone-Dependent Electron Transfer in the Respiratory Chain of Bacillus Subtilis by Membrane Energization. J. Bacteriol. 184, 5339– 5347, DOI: 10.1128/JB.184.19.5339-5347.2002
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Stimulation of menaquinone-dependent electron transfer in the respiratory chain of Bacillus subtilis by membrane energization
Azarkina, N.; Konstantinov, A. A.
Journal of Bacteriology (2002), 184 (19), 5339-5347CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
At a pH of ≤7, respiration of Bacillus subtilis cells on endogenous substrates shut down almost completely upon addn. of an uncoupler (carbonyl cyanide m-chlorophenylhydrazone [CCCP]) and a K+-ionophore (valinomycin). The same effect was obsd. with cell spheroplasts lacking the cell wall. The concn. of CCCP required for 50% inhibition of the endogenous respiration in the presence of K+-valinomycin was below 100 nM. Either CCCP or valinomycin alone was much less efficient than the combination of the two. The inhibitory effect was easily reversible and depended specifically on the H+ and K+ concns. in the medium. Similar inhibition was obsd. with respect to the redn. of the artificial electron acceptors 2,6-dichlorophenolindophenol (DCPIP) and N,N,N',N'-tetramethyl-p-phenylenediamine cation (TMPD+), which intercept reducing equiv. at the level of menaquinol. Oxidn. of the reduced DCPIP or TMPD in the bacterial cells was not sensitive to uncoupling. The same loss of the electron transfer activities as induced by the uncoupling was obsd. upon disruption of the cells during isolation of the membranes; the residual activities were not further inhibited by the uncoupler and ionophores. We conclude that the menaquinone-dependent electron transfer in the B. subtilis respiratory chain is facilitated, thermodynamically or kinetically, by membrane energization. A requirement for an energized state of the membrane is not a specific feature of succinate oxidn., as proposed in the literature, since it was also obsd. in a mutant of B. subtilis lacking succinate:quinone reductase as well as for substrates other than succinate. Possible mechanisms of the energy-dependent regulation of menaquinone-dependent respiration in B. subtilis are discussed.
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Schirawski, J. and Unden, G. (1998) Menaquinone-Dependent Succinate Dehydrogenase of Bacteria Catalyzes Reversed Electron Transport Driven by the Proton Potential. Eur. J. Biochem. 257, 210– 215, DOI: 10.1046/j.1432-1327.1998.2570210.x
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Menaquinone-dependent succinate dehydrogenase of bacteria catalyzes reversed electron transport driven by the proton potential
Schirawski, Jan; Unden, Gottfried
European Journal of Biochemistry (1998), 257 (1), 210-215CODEN: EJBCAI; ISSN:0014-2956. (Springer-Verlag)
Succinate dehydrogenases from bacteria and archaea using menaquinone (MK) as an electron acceptor (succinate/menaquinone oxidoreductases) contain, or are predicted to contain, two heme-B groups in the membrane-anchoring protein(s), located close to opposite sides of the membrane. All succinate/ubiquinone oxidoreductases, however, contain only one heme-B mol. In Bacillus subtilis and other bacteria that use MK as the respiratory quinone, the succinate oxidase activity (succinate→O2), and the succinate/menaquinone oxidoreductase activity were specifically inhibited by uncoupler (CCCP, carbonyl cyanide m-chlorophenylhydrazone) or by agents dissipating the membrane potential (valinomycin). Other parts of the respiratory chains were not affected by the agents. Succinate oxidase or succinate/ubiquinone oxidoreductase from bacteria using ubiquinone as an acceptor were not inhibited. We propose that the endergonic electron transport from succinate (Eo' = +30 mV) to MK (Eo'≃ -80mV) in succinate/menaquinone oxidoreductase includes a reversed electron transport across the cytoplasmic membrane from the inner (neg.) to the outer (pos.) side via the two heme-B groups. The reversed electron transport is driven by the proton or elec. potential, which provides the driving force for MK redn.
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Mesa-Arango, A. C., Trevijano-Contador, N., Roman, E., Sanchez-Fresneda, R., Casas, C., Herrero, E., Arguelles, J. C., Pla, J., Cuenca-Estrella, M., and Zaragoza, O. (2014) The Production of Reactive Oxygen Species Is a Universal Action Mechanism of Amphotericin B against Pathogenic Yeasts and Contributes to the Fungicidal Effect of This Drug. Antimicrob. Agents Chemother. 58, 6627– 6638, DOI: 10.1128/AAC.03570-14
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The production of reactive oxygen species is a universal action mechanism of amphotericin B against pathogenic yeasts and contributes to the fungicidal effect of this drug
Mesa-Arango, Ana Cecilia; Trevijano-Contador, Nuria; Roman, Elvira; Sanchez-Fresneda, Ruth; Casas, Celia; Herrero, Enrique; Arguelles, Juan Carlos; Pla, Jesus; Cuenca-Estrella, Manuel; Zaragoza, Oscar
Antimicrobial Agents and Chemotherapy (2014), 58 (11), 6627-6638, 13 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Amphotericin B (AMB) is an antifungal drug that binds to ergosterol and forms pores at the cell membrane, causing the loss of ions. In addn., AMB induces the accumulation of reactive oxygen species (ROS), and although these mols. have multiple deleterious effects on fungal cells, their specific role in the action mechanism of AMB remains unknown. In this work, we studied the role of ROS in the action mechanism of AMB. We detd. the intracellular induction of ROS in 44 isolates of different pathogenic yeast species (Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, Candida krusei, Cryptococcus neoformans and Cryptococcus gattii). We also characterized the prodn. of ROS in AMB-resistant isolates. We found that AMB induces the formation of ROS in all the species tested. The inhibition of the mitochondrial respiratory chain by rotenone blocked the induction of ROS by AMB and provided protection from the killing action of the antifungal. Moreover, this phenomenon was absent in strains that displayed resistance to AMB. These strains showed an alteration in the respiration rate and mitochondrial membrane potential and also had higher catalase activity than that of the AMB-susceptible strains. Consistently, AMB failed to induce protein carbonylation in the resistant strains. Our data demonstrate that the prodn. of ROS by AMB is a universal and important action mechanism that is correlated with the fungicidal effect and might explain the low rate of resistance to the mol. Finally, these data provide an opportunity to design new strategies to improve the efficacy of this antifungal.
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Nagao, T., Nakayama-Imaohji, H., Elahi, M., Tada, A., Toyonaga, E., Yamasaki, H., Okazaki, K., Miyoshi, H., Tsuchiya, K., and Kuwahara, T. (2018) Lhistidine Augments the Oxidative Damage against Gram-negative Bacteria by Hydrogen Peroxide. Int. J. Mol. Med. 41, 2847– 2854, DOI: 10.3892/ijmm.2018.3473
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L-histidine augments the oxidative damage against Gram-negative bacteria by hydrogen peroxide
Nagao, Tamiko; Nakayama-Imaohji, Haruyuki; Elahi, Miad; Tada, Ayano; Toyonaga, Emika; Yamasaki, Hisashi; Okazaki, Katsuichiro; Miyoshi, Hirokazu; Tsuchiya, Koichiro; Kuwahara, Tomomi
International Journal of Molecular Medicine (2018), 41 (5), 2847-2854CODEN: IJMMFG; ISSN:1791-244X. (Spandidos Publications Ltd.)
Excessive damage to DNA and lipid membranes by reactive oxygen species reduces the viability of bacteria. In the present study, the proliferation of recA-deficient Escherichia coli strains was revealed to be inhibited by 1% L-histidine under aerobic conditions. This inhibition of proliferation was not obsd. under anaerobic conditions, indicating that L-histidine enhances oxidative DNA damage to E. coli cells. Reverse transcription-quant. polymerase chain reaction anal. demonstrated that the expression of recA in E. coli MG1655 increased ∼7-fold following treatment with 10 mM hydrogen peroxide (H2O2) plus 1% L-histidine, compared with that following exposure to H2O2 alone. L-histidine increased the genomic fragmentation of E. coli MG1655 following exposure to H2O2. In addn., L-histidine increased the generation of intracellular hydroxyl radicals in the presence of H2O2 in E. coli cells. Next, our group investigated the disinfection properties of the H2O2 and L-histidine combination. The combination of 100 mM H2O2 and 1.0% L-histidine significantly reduced the no. of viable cells of extended-spectrum-β-lactamase-producing E. coli and multidrug-resistant Pseudomonas aeruginosa, and this treatment was more effective than 100 mM H2O2 alone, but this effect was not obsd. in methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium. The combination of L-histidine and H2O2 may be a useful strategy to selectively increase the microbicidal activity of oxidative agents against Gram-neg. bacteria.
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Beavers, W. N. and Skaar, E. P. (2016) Neutrophil-Generated Oxidative Stress and Protein Damage in Staphylococcus Aureus. Pathog. Dis. 74, ftw060, DOI: 10.1093/femspd/ftw060
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Kirstein, J., Hoffmann, A., Lilie, H., Schmidt, R., Rubsamen-Waigmann, H., Brotz-Oesterhelt, H., Mogk, A., and Turgay, K. (2009) The Antibiotic ADEP Reprogrammes ClpP, Switching It from a Regulated to an Uncontrolled Protease. EMBO Mol. Med. 1, 37– 49, DOI: 10.1002/emmm.200900002
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The antibiotic ADEP reprogrammes ClpP, switching it from a regulated to an uncontrolled protease
Kirstein, Janine; Hoffmann, Anja; Lilie, Hauke; Schmidt, Ronny; Ruebsamen-Waigmann, Helga; Broetz-Oesterhelt, Heike; Mogk, Axel; Turgay, Kuersad
EMBO Molecular Medicine (2009), 1 (1), 37-49CODEN: EMMMAM; ISSN:1757-4684. (John Wiley & Sons Ltd.)
A novel class of antibiotic acyldepsipeptides (designated ADEPs) exerts its unique antibacterial activity by targeting the peptidase caseinolytic protease P (ClpP). ClpP forms proteolytic complexes with heat shock proteins (Hsp100) that select and process substrate proteins for ClpP-mediated degrdn. Here, we analyze the mol. mechanism of ADEP action and demonstrate that ADEPs abrogate ClpP interaction with cooperating Hsp100 ATPases (ATPases). Consequently, ADEP treated bacteria are affected in ClpP-dependent general and regulatory proteolysis. At the same time, ADEPs also activate ClpP by converting it from a tightly regulated peptidase, which can only degrade short peptides, into a proteolytic machinery that recognizes and degrades unfolded polypeptides. In vivo nascent polypeptide chains represent the putative primary target of ADEP-activated ClpP, providing a rationale for the antibacterial activity of the ADEPs. Thus, ADEPs cause a complete functional reprogramming of the Clp-protease complex.
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Klappenbach, J. A., Saxman, P. R., Cole, J. R., and Schmidt, T. M. (2001) Rrndb: The Ribosomal RNA Operon Copy Number Database. Nucleic Acids Res. 29, 181– 184, DOI: 10.1093/nar/29.1.181
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rrndb: the ribosomal RNA operon copy number database
Klappenbach, Joel A.; Saxman, Paul R.; Cole, James R.; Schmidt, Thomas M.
Nucleic Acids Research (2001), 29 (1), 181-184CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
The RRNA Operon Copy No. Database (rrndb) is an Internet-accessible database contg. annotated information on rRNA operon copy no. among prokaryotes. Gene redundancy is uncommon in prokaryotic genomes, yet the rRNA genes can vary from one to as many as 15 copies. Despite the widespread use of 16S rRNA gene sequences for identification of prokaryotes, information on the no. and sequence of individual rRNA genes in a genome is not readily accessible. In an attempt to understand the evolutionary implications of rRNA operon redundancy, we have created a phylogenetically arranged report on rRNA gene copy no. for a diverse collection of prokaryotic microorganisms. Each entry (organism) in the rrndb contains detailed information linked directly to external websites including the Ribosomal Database Project, GenBank, PubMed and several culture collections. Data contained in the rrndb will be valuable to researchers investigating microbial ecol. and evolution using 16S rRNA gene sequences. The rrndb web site is directly accessible on the WWW at http://rrndb.cme.msu.edu.
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Spratt, B. G. (1977) Properties of the Penicillin-Binding Proteins of Escherichia Coli K12. Eur. J. Biochem. 72, 341– 352, DOI: 10.1111/j.1432-1033.1977.tb11258.x
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Properties of the penicillin-binding proteins of Escherichia coli K12
Spratt, Brian G.
European Journal of Biochemistry (1977), 72 (2), 341-52CODEN: EJBCAI; ISSN:0014-2956.
C14-labeled benzyl penicillin (I) [61-33-6] bound to 6 proteins with mol. wts. of between 40000-91000 in the inner membrane of E. coli. Two addnl. binding proteins with mol. wts of 29000 and 32000 were sometimes detected. All proteins were accessible to I-14C in whole cells. Proteins 5 and 6 released bound I with half times of 5 and 19 min at 30° but the other binding proteins showed <50% release during a 60-min period at 30°. The rate of release of bound penicillin from some of the proteins was greatly stimulated by 2-mercaptoethanol and neutral hydroxylamine. Release of I-14C did not occur if the binding proteins were denatured in anionic detergent and so was probably enzymic. β-Lactams bound to either of a range of unlabeled penicillins and cephalosporins were studied by measuring their competition for the binding of I-14C to the 6 penicillin-binding proteins. Penicillins bound to all 6 proteins but that at least some cephalosporins failed to bind, or bound very slowly, to proteins 2, 5, and 6, although they bound to the other proteins. Since these cephalosporins inhibited cell division and caused cell lysis at concns. where no binding to proteins 2, 5, and 6 was detected, these latter proteins are apparently not the targets at which β-lactams bind to elicit the above physiol. responses.
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Denome, S. A., Elf, P. K., Henderson, T. A., Nelson, D. E., and Young, K. D. (1999) Escherichia Coli Mutants Lacking All Possible Combinations of Eight Penicillin Binding Proteins: Viability, Characteristics, and Implications for Peptidoglycan Synthesis. J. Bacteriol. 181, 3981– 3993, DOI: 10.1128/JB.181.13.3981-3993.1999
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Escherichia coli mutants lacking all possible combinations of eight penicillin binding proteins: viability, characteristics, and implications for peptidoglycan synthesis
Denome, Sylvia A.; Elf, Pamela K.; Henderson, Thomas A.; Nelson, David E.; Young, Kevin D.
Journal of Bacteriology (1999), 181 (13), 3981-3993CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
The penicillin binding proteins (PBPs) synthesize and remodel peptidoglycan, the structural component of the bacterial cell wall. Much is known about the biochem. of these proteins, but little is known about their biol. roles. To better understand the contributions these proteins make to the physiol. of Escherichia coli, we constructed 192 mutants from which eight PBP genes were deleted in every possible combination. The genes encoding PBPs 1a, 1b, 4, 5, 6, and 7, AmpC, and AmpH were cloned, and from each gene an internal coding sequence was removed and replaced with a kanamycin resistance cassette flanked by two res sites from plasmid RP4. Deletion of individual genes was accomplished by transferring each interrupted gene onto the chromosome of E. coli via λ phage transduction and selecting for kanamycin-resistant recombinants. Afterwards, the kanamycin resistance cassette was removed from each mutant strain by supplying ParA resolvase in trans, yielding a strain in which a long segment of the original PBP gene was deleted and replaced by an 8-bp res site. These kanamycin-sensitive mutants were used as recipients in further rounds of replacement mutagenesis, resulting in a set of strains lacking from one to seven PBPs. In addn., the dacD gene was deleted from two septuple mutants, creating strains lacking eight genes. The only deletion combinations not produced were those lacking both PBPs 1a and 1b because such a combination is lethal. Surprisingly, all other deletion mutants were viable even though, at the extreme, 8 of the 12 known PBPs had been eliminated. Furthermore, when both PBPs 2 and 3 were inactivated by the β-lactams mecillinam and aztreonam, resp., several mutants did not lyse but continued to grow as enlarged spheres, so that one mutant synthesized osmotically resistant peptidoglycan when only 2 of 12 PBPs (PBPs 1b and 1c) remained active. These results have important implications for current models of peptidoglycan biosynthesis, for understanding the evolution of the bacterial sacculus, and for interpreting results derived by mutating unknown open reading frames in genome projects. In addn., members of the set of PBP mutants will provide excellent starting points for answering fundamental questions about other aspects of cell wall metab.
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Kocaoglu, O. and Carlson, E. E. (2015) Profiling of β-Lactam Selectivity for Penicillin-Binding Proteins in Escherichia Coli Strain DC2. Antimicrob. Agents Chemother. 59, 2785– 2790, DOI: 10.1128/AAC.04552-14
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Profiling of β-lactam selectivity for penicillin-binding proteins in Escherichia coli strain DC2
Kocaoglu, Ozden; Carlson, Erin E.
Antimicrobial Agents and Chemotherapy (2015), 59 (5), 2785-2790CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Penicillin-binding proteins (PBPs) are integral players in bacterial cell division, and their catalytic activities can be monitored with β-lactam-contg. chem. probes. Compds. that target a single PBP could provide important information about the specific role(s) of each enzyme, making identification of such mols. important. The authors evaluated 22 com. available β-lactams for inhibition of the PBPs in live Escherichia coli strain DC2. Whole cells were titrated with β-lactam antibiotics and subsequently incubated with a fluorescent penicillin deriv., Bocillin-FL (Boc-FL), to label uninhibited PBPs. Protein visualization was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) sepn. and fluorescent scanning. The examd. β-lactams exhibited diverse PBP selectivities, with amdinocillin (mecillinam) showing selectivity for PBP2, aztreonam, piperacillin, cefuroxime, cefotaxime, and ceftriaxone for PBP3, and amoxicillin and cephalexin for PBP4. The remaining β-lactams did not block any PBPs in the DC2 strain of E. coli or inhibited more than one PBP at all examd. concns. in this Gram-neg. organism.
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Du, W., Brown, J. R., Sylvester, D. R., Huang, J., Chalker, A. F., So, C. Y., Holmes, D. J., Payne, D. J., and Wallis, N. G. (2000) Two Active Forms of UDP-N-Acetylglucosamine Enolpyruvyl Transferase in Gram-Positive Bacteria. J. Bacteriol. 182, 4146– 4152, DOI: 10.1128/JB.182.15.4146-4152.2000
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Two active forms of UDP-N-acetylglucosamine enolpyruvyl transferase in gram-positive bacteria
Du, Wensheng; Brown, James R.; Sylvester, Daniel R.; Huang, Jianzhong; Chalker, Alison F.; So, Chi Y.; Holmes, David J.; Payne, David J.; Wallis, Nicola G.
Journal of Bacteriology (2000), 182 (15), 4146-4152CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
Gene sequences encoding the enzymes UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) from many bacterial sources were analyzed. It was shown that whereas gram-neg. bacteria have only one murA gene, gram-pos. bacteria have two distinct genes encoding these enzymes which have possibly arisen from gene duplication. The two murA genes of the gram-pos. organism Streptococcus pneumoniae were studied further. Each of the murA genes was individually inactivated by allelic replacement. In each case, the organism was viable despite losing one of its murA genes. However, when attempts were made to construct a double-deletion strain, no mutants were obtained. This indicates that both genes encode active enzymes that can substitute for each other, but that the presence of a MurA function is essential to the organism. The two genes were further cloned and over-expressed, and the enzymes they encode were purified. Both enzymes catalyzed the transfer of enolpyruvate from phosphoenolpyruvate to UDP-N-acetylglucosamine, confirming they are both active UDP-N-acetylglucosamine enolpyruvyl transferases. The catalytic parameters of the two enzymes were similar, and they were both inhibited by the antibiotic fosfomycin.
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Noda, M., Kawahara, Y., Ichikawa, A., Matoba, Y., Matsuo, H., Lee, D.-G., Kumagai, T., and Sugiyama, M. (2004) Self-Protection Mechanism in D-Cycloserine-Producing Streptomyces Lavendulae. Gene Cloning, Characterization, and Kinetics of Its Alanine Racemase and D-Alanyl-D-Alanine Ligase, Which Are Target Enzymes of D-Cycloserine. J. Biol. Chem. 279, 46143– 46152, DOI: 10.1074/jbc.M404603200
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Self-protection Mechanism in D-Cycloserine-producing Streptomyces lavendulae. Gene cloning, characterization, and kinetics of its alanine racemase and D-alanyl-D-alanine ligase, which are target enzymes of D-cycloserine
Noda, Masafumi; Kawahara, Yumi; Ichikawa, Azusa; Matoba, Yasuyuki; Matsuo, Hiroaki; Lee, Dong-Geun; Kumagai, Takanori; Sugiyama, Masanori
Journal of Biological Chemistry (2004), 279 (44), 46143-46152CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
An antibiotic, D-cycloserine (DCS), inhibits the catalytic activities of alanine racemase (ALR) and D-alanyl-D-alanine ligase (DDL), which are necessary for the biosynthesis of the bacterial cell wall. In this study, we cloned both genes encoding ALR and DDL, designated alrS and ddlS, resp., from DCS-producing Streptomyces lavendulae ATCC25233. Each gene product was purified to homogeneity and characterized. Escherichia coli, transformed with a pET vector carrying alrS or ddlS, displays higher resistance to DCS than the same host carrying the E. coli ALR- or DDL-encoded gene inserted into the pET vector. Although the S. lavendulae DDL was competitively inhibited by DCS, the Ki value (920 μM) was obviously higher (40∼100-fold) than those for E. coli DdlA (9 μM) or DdlB (27 μM). The high Ki value of the S. lavendulae DDL suggests that the enzyme may be a self-resistance determinant in the DCS-producing microorganism. Kinetic studies for the S. lavendulae ALR suggest that the time-dependent inactivation rate of the enzyme by DCS is absolutely slower than that of the E. coli ALR. We conclude that ALR from DCS-producing S. lavendulae is also one of the self-resistance determinants.
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Rudolf, J. D., Dong, L.-B., and Shen, B. (2017) Platensimycin and Platencin: Inspirations for Chemistry, Biology, Enzymology, and Medicine. Biochem. Pharmacol. 133, 139– 151, DOI: 10.1016/j.bcp.2016.11.013
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Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine
Rudolf, Jeffrey D.; Dong, Liao-Bin; Shen, Ben
Biochemical Pharmacology (Amsterdam, Netherlands) (2017), 133 (), 139-151CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clin. antibiotics. Their unparalleled structural and chem. diversities provide a basis to investigate fundamental biol. processes while providing access to a tremendous amt. of chem. space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biol. activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis. The elucidation of their unique biochem. mode of action, structure-activity relationships, and pharmacokinetics is presented to highlight key aspects of their biol. activities. It then presents an overview of how microbial genomics has impacted the field of PTM and PTN and revealed paradigm-shifting discoveries in terpenoid biosynthesis, fatty acid metab., and antibiotic and antidiabetic therapies. It concludes with a discussion covering the future perspectives of PTM and PTN in regard to natural products discovery, bacterial diterpenoid biosynthesis, and the pharmaceutical promise of PTM and PTN as antibiotics and for the treatment of metabolic disorders. PTM and PTN have inspired new discoveries in chem., biol., enzymol., and medicine and will undoubtedly continue to do so.
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Jayasuriya, H., Herath, K. B., Zhang, C., Zink, D. L., Basilio, A., Genilloud, O., Diez, M. T., Vicente, F., Gonzalez, I., Salazar, O., Pelaez, F., Cummings, R., Ha, S., Wang, J., and Singh, S. B. (2007) Isolation and Structure of Platencin: A FabH and FabF Dual Inhibitor with Potent Broad-Spectrum Antibiotic Activity. Angew. Chem., Int. Ed. 46, 4684– 4688, DOI: 10.1002/anie.200701058
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Isolation and structure of Platencin: a FabH and FabF dual inhibitor with potent broad-spectrum antibiotic activity
Jayasuriya, Hiranthi; Herath, Kithsiri B.; Zhang, Chaowei; Zink, Deborah L.; Basilio, Angela; Genilloud, Olga; Diez, Maria Teresa; Vicente, Francisca; Gonzalez, Ignacio; Salazar, Oscar; Pelaez, Fernando; Cummings, Richard; Ha, Sookhee; Wang, Jun; Singh, Sheo B.
Angewandte Chemie, International Edition (2007), 46 (25), 4684-4688CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Two birds with one stone: platencin is a novel and potent broad-spectrum Gram-pos. antibiotic. Whereas platensimycin is a selective inhibitor of FabF, platencin exerts its activity by a novel mode of action by dual inhibition of FabH and FabF. The authors describe the isolation, structure elucidation, and addnl. biol. activity of platencin as well as a modeling-based rationale for the differences in activity between platencin and platensimycin.
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Wang, J., Kodali, S., Lee, S. H., Galgoci, A., Painter, R., Dorso, K., Racine, F., Motyl, M., Hernandez, L., Tinney, E. (2007) Discovery of Platencin, a Dual FabF and FabH Inhibitor with in Vivo Antibiotic Properties. Proc. Natl. Acad. Sci. U. S. A. 104, 7612– 7616, DOI: 10.1073/pnas.0700746104
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Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties
Wang, Jun; Kodali, Srinivas; Lee, Sang Ho; Galgoci, Andrew; Painter, Ronald; Dorso, Karen; Racine, Fred; Motyl, Mary; Hernandez, Lorraine; Tinney, Elizabeth; Colletti, Steven L.; Herath, Kithsiri; Cummings, Richard; Salazar, Oscar; Gonzalez, Ignacio; Basilio, Angela; Vicente, Francisca; Genilloud, Olga; Pelaez, Fernando; Jayasuriya, Hiranthi; Young, Katherine; Cully, Doris F.; Singh, Sheo B.
Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (18), 7612-7616CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently the authors reported the discovery of platensimycin by screening natural product exts. using a target-based whole-cell strategy with antisense silencing technol. in concert with cell free biochem. validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chem. and biol. related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-pos. antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Platencin shows potent in vivo efficacy without any obsd. toxicity. It targets 2 essential proteins, β-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC50 values of 1.95 and 3.91 μg/mL, resp., whereas platensimycin targets only FabF (IC50 = 0.13 μg/mL) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by this antisense differential sensitivity whole-cell screening paradigm.
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Velkov, T., Roberts, K. D., Nation, R. L., Thompson, P. E., and Li, J. (2013) Pharmacology of Polymyxins: New Insights into an “old” Class of Antibiotics. Future Microbiol. 8, 711– 724, DOI: 10.2217/fmb.13.39
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Pharmacology of polymyxins: new insights into an old' class of antibiotics
Velkov, Tony; Roberts, Kade D.; Nation, Roger L.; Thompson, Philip E.; Li, Jian
Future Microbiology (2013), 8 (6), 711-724CODEN: FMUIAR; ISSN:1746-0913. (Future Medicine Ltd.)
A review. Increasing antibiotic resistance in Gram-neg. bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these superbugs' in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-neg. bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chem., mechanisms of antibacterial activity and resistance, structure-activity relationships and pharmacokinetics/pharmacodynamics. In the Bad Bugs, No Drugs' era, we must pursue structure-activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-neg. superbugs'. Before new antibiotics become available, we must optimize the clin. use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.
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Fu, L., Wan, M., Zhang, S., Gao, L., and Fang, W. (2020) Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer. Biophys. J. 118, 138– 150, DOI: 10.1016/j.bpj.2019.11.008
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Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer
Fu, Lei; Wan, Mingwei; Zhang, Shan; Gao, Lianghui; Fang, Weihai
Biophysical Journal (2020), 118 (1), 138-150CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
Multidrug-resistant Gram-neg. bacteria have increased the prevalence of a variety of serious diseases in modern times. Polymyxins are used as the last-line therapeutic options for the treatment of infections. However, the mechanism of action of polymyxins remains in dispute. In this work, we used a coarse-grained mol. dynamics simulation to investigate the mechanism of the cationic antimicrobial peptide polymyxin B (PmB) interacting with both the inner and outer membrane models of bacteria. Our results show that the binding of PmB disturbs the outer membrane by displacing the counterions, decreasing the orientation order of the lipopolysaccharide tail, and creating more lipopolysaccharide packing defects. Upon binding onto the inner membrane, in contrast to the traditional killing mechanism that antimicrobial peptides usually use to induce holes in the membrane, PmBs do not permeabilize the inner membrane but stiffen it by filling up the lipid packing defect, increasing the lipid tail order and the membrane bending rigidity as well as restricting the lipid diffusion. PmBs also mediate intermembrane contact and adhesion. These joint effects suggest that PmBs deprive the biol. activity of Gram-neg. bacteria by sterilizing the cell.
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Deris, Z. Z., Akter, J., Sivanesan, S., Roberts, K. D., Thompson, P. E., Nation, R. L., Li, J., and Velkov, T. (2014) A Secondary Mode of Action of Polymyxins against Gram-Negative Bacteria Involves the Inhibition of NADH-Quinone Oxidoreductase Activity. J. Antibiot. 67, 147– 151, DOI: 10.1038/ja.2013.111
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A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity
Deris, Zakuan Z.; Akter, Jesmin; Sivanesan, Sivashangarie; Roberts, Kade D.; Thompson, Philip E.; Nation, Roger L.; Li, Jian; Velkov, Tony
Journal of Antibiotics (2014), 67 (2), 147-151CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
Polymyxin B and colistin were examd. for their ability to inhibit the type II NADH-quinone oxidoreductases (NDH-2) of three species of Gram-neg. bacteria. Polymyxin B and colistin inhibited the NDH-2 activity in prepns. from all of the isolates in a concn.-dependent manner. The mechanism of NDH-2 inhibition by polymyxin B was investigated in detail with Escherichia coli inner membrane prepns. and conformed to a mixed inhibition model with respect to ubiquinone-1 and a non-competitive inhibition model with respect to NADH. These suggest that the inhibition of vital respiratory enzymes in the bacterial inner membrane represents one of the secondary modes of action for polymyxins.
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Stuart, M. C., Kouimtzi, M., and Hill, S. (2009) WHO Model Formulary 2008, WHO, Geneva.
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Arbiser, J. L. and Moschella, S. L. (1995) Clofazimine: A Review of Its Medical Uses and Mechanisms of Action. J. Am. Acad. Dermatol. 32, 241– 247, DOI: 10.1016/0190-9622(95)90134-5
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Clofazimine: a review of its medical uses and mechanisms of action
Arbiser J L; Moschella S L
Journal of the American Academy of Dermatology (1995), 32 (2 Pt 1), 241-7 ISSN:0190-9622.
Clofazimine has been in clinical use for almost 40 years, but little is known of its mechanism of action. The primary indication for clofazimine is multibacillary leprosy, but it is useful in several infectious and noninfectious diseases, such as typical myocobacterial infections, rhinoscleroma, pyoderma gangrenosum, necrobiosis lipoidica, severe acne, pustular psoriasis, and discoid lupus erythematosus. Postulated mechanisms of action include intercalation of clofazimine with bacterial DNA and increasing levels of cellular phospholipase A2. Clinical experience, possible mechanisms of action, and side effects of clofazimine are summarized.
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Lesnik, U., Lukezic, T., Podgorsek, A., Horvat, J., Polak, T., Sala, M., Jenko, B., Harmrolfs, K., Ocampo-Sosa, A., Martinez-Martinez, L., Herron, P. R., Fujs, S., Kosec, G., Hunter, I. S., Muller, R., and Petkovic, H. (2015) Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering. Angew. Chem., Int. Ed. 54, 3937– 3940, DOI: 10.1002/anie.201411028
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Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering
Lesnik, Urska; Lukezic, Tadeja; Podgorsek, Ajda; Horvat, Jaka; Polak, Tomaz; Sala, Martin; Jenko, Branko; Harmrolfs, Kirsten; Ocampo-Sosa, Alain; Martinez-Martinez, Luis; Herron, Paul R.; Fujs, Stefan; Kosec, Gregor; Hunter, Iain S.; Mueller, Rolf; Petkovic, Hrvoje
Angewandte Chemie, International Edition (2015), 54 (13), 3937-3940CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacol. properties could not be addressed at the time. It is demonstrated here that reviving such compds. through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad-spectrum antibiotic lead was generated with significantly improved activity, including against all Gram-neg. pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chem. modification, it is a platform for further development through medicinal chem. and genetic engineering.
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Herrmann, J., Lukezic, T., Kling, A., Baumann, S., Huttel, S., Petkovic, H., and Muller, R. (2016) Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies. Curr. Top. Microbiol. Immunol. 398, 339– 363, DOI: 10.1007/82_2016_498
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Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies
Herrmann, Jennifer; Lukezic, Tadeja; Kling, Angela; Baumann, Sascha; Huettel, Stephan; Petkovic, Hrvoje; Mueller, Rolf
Current Topics in Microbiology and Immunology (2016), 398 (How to Overcome the Antibiotic Crisis), 339-363CODEN: CTMIA3; ISSN:2196-9965. (Springer GmbH)
Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Center for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery. In particular, we will exemplarily illustrate three approaches: (1) Current sources for novel compds. are mainly soil-dwelling bacteria. In the course of our antimicrobial discovery program, a biodiverse collection of myxobacterial strains has been established and screened for antibiotic activities. Based on this effort, one successful example is presented in this chapter: Antibacterial cystobactamids were discovered and their mol. target, the DNA gyrase, was identified soon after the anal. of myxobacterial self-resistance making use of the information found in the resp. biosynthesis gene cluster. (2) Besides our focus on novel natural products, we also apply strategies to further develop either neglected drugs or widely used antibiotics for which development of resistance in the clin. setting is an issue: Antimycobacterial griselimycins were first described in the 1960s but their development and use in tuberculosis therapy was not further pursued. We show how a griselimycin deriv. with improved pharmacokinetic properties and enhanced potency against Mycobacterium tuberculosis revealed and validated a novel target for antibacterial therapy, the DNA sliding clamp. (3) In a third approach, biosynthetic engineering was used to modify and optimize natural products regarding their pharmaceutical properties and their prodn. scale: The atypical tetracycline chelocardin is a natural product scaffold that was modified to yield a more potent deriv. exhibiting activity against multidrug-resistant pathogens. This was achieved by genetic engineering of the producer strain and the resulting compd. is now subject to further optimization by medicinal chem. approaches.
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Stepanek, J. J., Lukezic, T., Teichert, I., Petkovic, H., and Bandow, J. E. (2016) Dual Mechanism of Action of the Atypical Tetracycline Chelocardin. Biochim. Biophys. Acta, Proteins Proteomics 1864, 645– 654, DOI: 10.1016/j.bbapap.2016.03.004
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Dual mechanism of action of the atypical tetracycline chelocardin
Stepanek, Jennifer J.; Lukezic, Tadeja; Teichert, Ines; Petkovic, Hrvoje; Bandow, Julia E.
Biochimica et Biophysica Acta, Proteins and Proteomics (2016), 1864 (6), 645-654CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B. V.)
FR OLClassical tetracyclines targeting the protein biosynthesis machinery are commonly applied in human and veterinary medicine. OLtThe development and spread of resistance seriously compromise the successful treatment of bacterial infections. The atypical tetracycline chelocardin holds promise as it retains activity against tetracycline-resistant strains. It has been suggested that chelocardin targets the bacterial membrane, thus differing in mode of action from that of classical tetracyclines. The authors investigated the mechanism of action of chelocardin using global proteome anal. The proteome profiles after sublethal chelocardin stress were compared to a ref. compendium contg. antibiotic response profiles of Bacillus subtilis. This approach revealed a concn.-dependent dual mechanism of action. At low concns., like classical tetracyclines, chelocardin induces the proteomic signature for peptidyltransferase inhibition, demonstrating that protein biosynthesis inhibition is the dominant physiol. challenge. At higher concns., B. subtilis mainly responds to membrane stress indicating that at clin. relevant concns. the membrane is the main antibiotic target of chelocardin. Studying the effects on the membrane in more detail, it was found that chelocardin causes membrane depolarization but does not lead to formation of large pores. It is concluded that at growth inhibiting doses chelocardin not only targets protein biosynthesis but also corrupts the integrity of the bacterial membrane. This dual mechanism of action might prove beneficial in slowing the development of new resistance mechanisms against this atypical tetracycline.
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Herskovits, A. A. and Bibi, E. (2000) Association of Escherichia Coli Ribosomes with the Inner Membrane Requires the Signal Recognition Particle Receptor but Is Independent of the Signal Recognition Particle. Proc. Natl. Acad. Sci. U. S. A. 97, 4621– 4626, DOI: 10.1073/pnas.080077197
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Association of Escherichia coli ribosomes with the inner membrane requires the signal recognition particle receptor but is independent of the signal recognition particle
Herskovits, Anat A.; Bibi, Eitan
Proceedings of the National Academy of Sciences of the United States of America (2000), 97 (9), 4621-4626CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
In mammalian cells, as well as Escherichia coli, ribosomes translating membrane proteins interact cotranslationally with translocons in the membrane, and this interaction is essential for proper insertion of nascent polypeptides into the membrane. Both the signal recognition particle (SRP) and its receptor (SR) are required for functional assocn. of ribosomes translating integral membrane proteins with the translocon. Herein, we confirm that membrane targeting of E. coli ribosomes requires the prokaryotic SRα homolog FtsY in vivo. Surprisingly, however, depletion of the E. coli SRP54 homolog (Ffh) has no significant effect on binding of ribosomes to the membrane, although Ffh depletion is detrimental to growth. These and other observations suggest that, in E. coli, SRP may operate downstream of SR-mediated targeting of ribosomes to the plasma membrane.
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Ruhr, E. and Sahl, H. G. (1985) Mode of Action of the Peptide Antibiotic Nisin and Influence on the Membrane Potential of Whole Cells and on Cytoplasmic and Artificial Membrane Vesicles. Antimicrob. Agents Chemother. 27, 841– 845, DOI: 10.1128/AAC.27.5.841
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Mode of action of the peptide antibiotic nisin and influence on the membrane potential of whole cells and on cytoplasmic and artificial membrane vesicles
Ruhr, Elke; Sahl, Hans G.
Antimicrobial Agents and Chemotherapy (1985), 27 (5), 841-5CODEN: AMACCQ; ISSN:0066-4804.
The peptide antibiotic nisin caused a rapid efflux of amino acids and Rb+ from the cytoplasm of gram-pos. bacteria (Staphylococcus cohnii 22, Bacillus subtilis W 23, Micrococcus luteus ATCC 4698, and Streptococcus zymogenes 24). The antibiotic strongly decreased the membrane potential of cells as judged by the distribution of the lipophilic tetraphenylphosphonium cation. Ascorbate-phenazine methosulfate-driven transport of L-proline by cytoplasmic membrane vesicles was blocked after addn. of nisin, and accumulated amino acids were released from the vesicles. Soybean phospholipid (asolectin) vesicles were not affected by nisin. Apparently, the cytoplasmic membrane is the primary target and membrane disruption accounts for the bactericidal action of nisin.
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Breukink, E., Wiedemann, I., van Kraaij, C., Kuipers, O. P., Sahl, H. G., and de Kruijff, B. (1999) Use of the Cell Wall Precursor Lipid II by a Pore-Forming Peptide Antibiotic. Science 286, 2361– 2364, DOI: 10.1126/science.286.5448.2361
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Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic
Breukink, E.; Wiedemann, I.; Van Kraaij, C.; Kuipers, O. P.; Sahl, H.-G.; De Kruijff, B.
Science (Washington, D. C.) (1999), 286 (5448), 2361-2364CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Resistance to antibiotics is increasing in some groups of clin. important pathogens. For instance, high vancomycin resistance has emerged in enterococci. Promising alternative antibiotics are the peptide antibiotics, abundant in host defense systems, which kill their targets by permeabilizing the plasma membrane. These peptides generally do not act via specific receptors and are active in the micromolar range. Here it is shown that vancomycin and the antibacterial peptide nisin Z use the same target: the membrane-anchored cell wall precursor lipid II. Nisin combines high affinity for lipid II with its pore-forming ability, thus causing the peptide to be highly active (in the nanomolar range).
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Hasper, H. E., de Kruijff, B., and Breukink, E. (2004) Assembly and Stability of Nisin-Lipid II Pores. Biochemistry 43, 11567– 11575, DOI: 10.1021/bi049476b
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Assembly and Stability of Nisin-Lipid II Pores
Hasper, Hester Emilie; De Kruijff, Ben; Breukink, Eefjan
Biochemistry (2004), 43 (36), 11567-11575CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
The peptide antibiotic nisin was the first reported example of an antibiotic that kills bacteria via targeted pore formation. The specific target of nisin is Lipid II, an essential intermediate in the bacterial cell-wall synthesis. High-affinity binding of the antibiotic to Lipid II is followed by rapid permeabilization of the membrane. Here, we investigated the assembly and stability of nisin-Lipid II pore complexes by means of pyrene fluorescence and CD. We demonstrated that nisin uses all available Lipid II mols. in the membrane to form pore complexes. The pore complexes have a uniform structure and consist of 8 nisin and 4 Lipid II mols. Moreover, the pores displayed a remarkable stability, because they were able to resist the solubilization of the membrane environment by mild detergents. Similar expts. with [N20P/M21P]nisin showed that the hinge region is essential for the assembly into stable pore complexes. The new insights were used to propose a refined model for nisin pore formation.
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’t Hart, P., Oppedijk, S. F., Breukink, E., and Martin, N. I. (2016) New Insights into Nisin’s Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues. Biochemistry 55, 232– 237, DOI: 10.1021/acs.biochem.5b01173
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New Insights into Nisin's Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues
't Hart, Peter; Oppedijk, Sabine F.; Breukink, Eefjan; Martin, Nathaniel I.
Biochemistry (2016), 55 (1), 232-237CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
Nisin is the preeminent lantibiotic, and to date its antibacterial mechanism has been investigated using a variety of techniques. While nisin's lipid II-mediated mode of action is well-established, a detailed anal. of the thermodn. parameters governing this interaction has not been previously reported. We here describe an approach employing isothermal titrn. calorimetry to directly measure the affinity of nisin for lipid II and a no. of synthetic lipid II precursors and analogs. Our measurements confirm the pyrophosphate unit of lipid II as the primary site of nisin binding and also indicate that the complete MurNAc moiety is required for a high-affinity interaction. Addnl., we find that while the pentapeptide unit of the lipid II mol. is not required for strong binding by nisin, it does play an important role in stabilizing the subsequently formed nisin-lipid II pore complex, albeit at an entropic cost. The anchoring of lipid II in a membrane environment was also found to play a significant role in enhancing nisin binding and is required in order to achieve a high-affinity interaction.
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Bonev, B. B., Chan, W. C., Bycroft, B. W., Roberts, G. C., and Watts, A. (2000) Interaction of the Lantibiotic Nisin with Mixed Lipid Bilayers: A 31P and 2H NMR Study. Biochemistry 39, 11425– 11433, DOI: 10.1021/bi0001170
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Interaction of the Lantibiotic Nisin with Mixed Lipid Bilayers: A 31P and 2H NMR Study
Bonev, Boyan B.; Chan, Weng C.; Bycroft, Barrie W.; Roberts, Gordon C. K.; Watts, Anthony
Biochemistry (2000), 39 (37), 11425-11433CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
Nisin is a pos. charged antibacterial peptide which binds to the neg. charged membranes of Gram-pos. bacteria. The initial interaction of the peptide with model membranes of neutral (phosphatidylcholine) and neg. charged (phosphatidylcholine/phosphatidylglycerol) model lipid membranes was studied using nonperturbing solid state magic angle spinning (MAS) 31P NMR and 2H wide-line NMR. In the presence of nisin, the coexistence of two bilayer lipid environments was obsd. both in charged and in neutral membranes. One lipid environment was found to be assocd. with lipid directly interacting with nisin and one with noninteracting lipid. Solid state 31P MAS NMR results show that the acidic membrane lipid component partitions preferentially into the nisin-assocd. environment. Deuterium NMR (2H NMR) of the selectively headgroup-labeled acidic lipid provides further evidence of a strong interaction between the charged lipid component and the peptide. The segregation of acidic lipid into the nisin-bound environment was quantified from 2H NMR measurements of selectively headgroup-deuterated neutral lipid. It is suggested that the obsd. lipid partitioning in the presence of nisin is driven, at least initially, by electrostatic interactions. 2H NMR measurements from chain-perdeuterated neutral lipids indicate that nisin perturbs the hydrophobic region of both charged and neutral bilayers.
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Christ, K., Al-Kaddah, S., Wiedemann, I., Rattay, B., Sahl, H.-G., and Bendas, G. (2008) Membrane Lipids Determine the Antibiotic Activity of the Lantibiotic Gallidermin. J. Membr. Biol. 226, 9– 16, DOI: 10.1007/s00232-008-9134-4
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Membrane lipids determine the antibiotic activity of the lantibiotic gallidermin
Christ, Katrin; Al-Kaddah, Saad; Wiedemann, Imke; Rattay, Bernd; Sahl, Hans-Georg; Bendas, Gerd
Journal of Membrane Biology (2008), 226 (1-3), 9-16CODEN: JMBBBO; ISSN:0022-2631. (Springer)
Lantibiotics, a group of lanthionine-contg. peptides, display their antibiotic activity by combining different killing mechanisms within one mol. The prototype lantibiotic nisin was shown to possess both inhibition of peptidoglycan synthesis and pore formation in bacterial membranes by interacting with lipid II. Gallidermin, which shares the lipid II binding motif with nisin but has a shorter mol. length, differed from nisin in pore formation in several strains of bacteria. To simulate the mode of action, we applied cyclic voltammetry and quartz crystal microbalance to correlate pore formation with lipid II binding kinetics of gallidermin in model membranes. The inability of gallidermin to form pores in DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) (C18/1) and DPoPC (1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine) (C16/1) membranes was related to the membrane thickness. For a better simulation of bacterial membrane characteristics, two different phospholipids with branched fatty acids were incorporated into the DPoPC matrix. Phospholipids with Me branches in the middle of the fatty acid chains favored a lipid II-independent DPoPC permeabilization by gallidermin, while long-branched phospholipids in which the branch is placed near the hydrophilic region induced an identical lipid II-dependent pore formation of gallidermin and nisin. Obviously, the branched lipids altered lipid packing and reduced the membrane thickness. Therefore, the duality of gallidermin activity (pore formation and inhibition of the cell wall synthesis) seems to be balanced by the bacterial membrane compn.
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Muraih, J. K. and Palmer, M. (2012) Estimation of the Subunit Stoichiometry of the Membrane-Associated Daptomycin Oligomer by FRET. Biochim. Biophys. Acta, Biomembr. 1818, 1642– 1647, DOI: 10.1016/j.bbamem.2012.02.019
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Estimation of the subunit stoichiometry of the membrane-associated daptomycin oligomer by FRET
Muraih, Jawad K.; Palmer, Michael
Biochimica et Biophysica Acta, Biomembranes (2012), 1818 (7), 1642-1647CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Daptomycin is a lipopeptide antibiotic that kills Gram-pos. bacteria by depolarizing their cell membranes. This antibacterial action of daptomycin is correlated with the formation of membrane-assocd. oligomers. We here examine the no. of subunits contained in one oligomer using fluorescence resonance energy transfer (FRET). The results suggest that the oligomer contains approx. 6-7 subunits, or possibly twice this no. if it spans both membrane monolayers.
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Muraih, J. K., Pearson, A., Silverman, J., and Palmer, M. (2011) Oligomerization of Daptomycin on Membranes. Biochim. Biophys. Acta, Biomembr. 1808, 1154– 1160, DOI: 10.1016/j.bbamem.2011.01.001
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Oligomerization of daptomycin on membranes
Muraih, Jawad K.; Pearson, Andre; Silverman, Jared; Palmer, Michael
Biochimica et Biophysica Acta, Biomembranes (2011), 1808 (4), 1154-1160CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Daptomycin (I) is a lipopeptide antibiotic that kills Gram-pos. bacteria by membrane depolarization. While it has long been assumed that the mode of action of I involves the formation of membrane-assocd. oligomers, this has so far not been exptl. demonstrated. Here, the authors used FRET between native I and an NBD-labeled I deriv. to show that such oligomerization indeed occurred. The oligomers were obsd. in the presence of Ca2+ on membrane vesicles isolated from Bacillus subtilis, as well as on model membranes contg. the neg. charged phospholipid, phosphatidylglycerol. In contrast, oligomerization did not occur on membranes contg. phosphatidylcholine only, nor in soln. at micromolar I concns. The requirements for oligomerization of I resembled those previously reported for antibacterial activity, suggesting that oligomerization is necessary for the activity.
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Muraih, J. K., Harris, J., Taylor, S. D., and Palmer, M. (2012) Characterization of Daptomycin Oligomerization with Perylene Excimer Fluorescence: Stoichiometric Binding of Phosphatidylglycerol Triggers Oligomer Formation. Biochim. Biophys. Acta, Biomembr. 1818, 673– 678, DOI: 10.1016/j.bbamem.2011.10.027
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Characterization of daptomycin oligomerization with perylene excimer fluorescence: Stoichiometric binding of phosphatidylglycerol triggers oligomer formation
Muraih, Jawad K.; Harris, Jesse; Taylor, Scott D.; Palmer, Michael
Biochimica et Biophysica Acta, Biomembranes (2012), 1818 (3), 673-678CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Daptomycin is a lipopeptide antibiotic that binds to and depolarizes bacterial cell membranes. Its antibacterial activity requires calcium and correlates with the content of phosphatidylglycerol in the target membrane. Daptomycin has been shown to form oligomers on liposome membranes. We here use perylene excimer fluorescence to further characterize the membrane-assocd. oligomer. To this end, the N-terminal fatty acyl chain was replaced with perylene-butanoic acid. The perylene deriv. retains one third of the antibacterial activity of native daptomycin. On liposomes contg. phosphatidylcholine and phosphatidylglycerol, as well as on Bacillus subtilis cells, the perylene-labeled daptomycin forms excimers, which shows that the N-terminal acyl chains of neighboring oligomer subunits are in immediate contact with one another. In a lipid bicelle system, oligomer formation can be titrated with stoichiometric amts. of phosphatidylglycerol. Therefore, the interaction of daptomycin with a single mol. of phosphatidylglycerol is sufficient to trigger daptomycin oligomerization.
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Kreutzberger, M. A., Pokorny, A., and Almeida, P. F. (2017) Daptomycin-Phosphatidylglycerol Domains in Lipid Membranes. Langmuir 33, 13669– 13679, DOI: 10.1021/acs.langmuir.7b01841
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Daptomycin-Phosphatidylglycerol Domains in Lipid Membranes
Kreutzberger, Mark A.; Pokorny, Antje; Almeida, Paulo F.
Langmuir (2017), 33 (47), 13669-13679CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
Daptomycin is an acidic, 13-amino acid, cyclic polypeptide that contains a no. of nonproteinogenic residues and is modified at its N-terminus with a decanoyl chain. It has been in clin. use since 2003 against selected drug-resistant Staphylococcus aureus and Enterococcus spp infections. In vitro, daptomycin is active against Gram-pos. pathogens at low concns. but its antibiotic activity depends critically on the presence of Ca2+ ions. This dependence has been thought to arise from binding of 1 or 2 Ca2+ ions to daptomycin as a required step in its interaction with the bacterial membrane. Here, we investigated the interaction of daptomycin with giant unilamellar vesicles (GUVs) composed 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG). We used fluorescence confocal microscopy to monitor binding of the peptide to GUVs and to follow its effect on the membrane of the vesicle. We found that, in the absence of POPG or Ca2+, daptomycin did not bind measurably to the lipid membrane. In the presence of 20-30% PG in the membrane and 2 mM Ca2+, daptomycin induced the formation of membrane domains rich in acidic lipids. This effect was not induced by Ca2+ alone. In addn., daptomycin caused GUV collapse, but it did not translocate across the membrane to the inside of intact POPC:POPG vesicles. We concluded that pore formation is probably not the mechanism by which the peptide functions. On the other hand, we found that daptomycin coclustered with the anionic phospholipid POPG and the fluorescent probes used, leading to extensive formation of daptomycin-POPG domains in the membrane.
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Domalaon, R., Idowu, T., Zhanel, G. G., and Schweizer, F. (2018) Antibiotic Hybrids: The Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?. Clin. Microbiol. Rev. 31, e00077-17 DOI: 10.1128/CMR.00077-17
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Georgopapadakou, N. H., Bertasso, A., Chan, K. K., Chapman, J. S., Cleeland, R., Cummings, L. M., Dix, B. A., and Keith, D. D. (1989) Mode of Action of the Dual-Action Cephalosporin Ro 23–9424. Antimicrob. Agents Chemother. 33, 1067– 1071, DOI: 10.1128/AAC.33.7.1067
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Mode of action of the dual-action cephalosporin Ro 23-9424
Georgopapadakou, N. H.; Bertasso, A.; Chan, K. K.; Chapman, J. S.; Cleeland, R.; Cummings, L. M.; Dix, B. A.; Keith, D. D.
Antimicrobial Agents and Chemotherapy (1989), 33 (7), 1067-71CODEN: AMACCQ; ISSN:0066-4804.
Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biol. properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decompn. product, desacetyl cefotaxime, Ro 23-9424 bound at ≤2 μg/mL to the essential penicillin-bound proteins 1b and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureas. In E. coli, Ro 23-9424 produced filaments exclusively and decreased cell growth; cefotaxime produced both filaments and lysis. Like its decompn. product fleroxacin but unlike quinolone esters, Ro 23-9424 also inhibited replicative DNA biosynthesis in E. coli. In an E. coli strain lacking OmpF, growth continued after addn. of Ro 23-9424, decreased after addn. of cefotaxime, and stopped immediately after addn. of fleroxacin. The results, together with the chem. stability of Ro 23-9424 (half-life, ∼3 h at pH 7.4 and 37°), suggest that in E. coli the compd. acts initially as a cephalosporin with intrinsic activity comparable to that of cefotaxime but with poorer penetration. Subsequent to the decompn. of Ro 23-9424 to fleroxacin and desacetyl cefotaxime, quinolone activity appears. The in vitro antibacterial activity reflects both mechanisms of action.
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Stone, G. W., Zhang, Q., Castillo, R., Doppalapudi, V. R., Bueno, A. R., Lee, J. Y., Li, Q., Sergeeva, M., Khambatta, G., and Georgopapadakou, N. H. (2004) Mechanism of Action of NB2001 and NB2030, Novel Antibacterial Agents Activated by Beta-Lactamases. Antimicrob. Agents Chemother. 48, 477– 483, DOI: 10.1128/AAC.48.2.477-483.2004
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Mechanism of action of NB2001 and NB2030, novel antibacterial agents activated by β-lactamases
Stone, Geoffrey W.; Zhang, Qin; Castillo, Rosario; Doppalapudi, V. Ramana; Bueno, Analia R.; Lee, Jean Y.; Li, Qing; Sergeeva, Maria; Khambatta, Gody; Georgopapadakou, Nafsika H.
Antimicrobial Agents and Chemotherapy (2004), 48 (2), 477-483CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compds., NB2001 and NB2030 (I and II, resp.), contain a cephalosporin with a thienyl (I) or a tetrazole (II) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compds. exploit β-lactamases to release triclosan through hydrolysis of the β-lactam ring. Like cephalothin, I and II were hydrolyzed by class A β-lactamases (Escherichia coli TEM-1 and, to a lesser degree, Staphylococcus aureus PC1) and class C β-lactamases (Enterobacter cloacae P99 and E. coli AmpC) with comparable catalytic efficiencies (kcat/Km). They also bound to the penicillin-binding proteins of S. aureus and E. coli, but with reduced affinities relative to that of cephalothin. Accordingly, they produced a cell morphol. in E. coli consistent with the toxophore rather than the β-lactam being responsible for antibacterial activity. In biochem. assays, they inhibited the triclosan target enoyl reductase (FabI), with 50% inhibitory concns. being markedly reduced relative to that of free triclosan. The transport of I and II and triclosan was rapid, with significant accumulation of triclosan in both S. aureus and E. coli. Taken together, the results suggest that I and II act primarily as triclosan prodrugs in S. aureus and E. coli.
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Ma, Z. and Lynch, A. S. (2016) Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections. J. Med. Chem. 59, 6645– 6657, DOI: 10.1021/acs.jmedchem.6b00485
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Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections
Ma, Zhenkun; Lynch, Anthony Simon
Journal of Medicinal Chemistry (2016), 59 (14), 6645-6657CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The clin. management of prosthetic joint infections and other persistent bacterial infections represents a major unmet medical need. The rifamycins are one of the most potent antibiotic classes against persistent bacterial infections, but bacteria can develop resistance to rifamycins rapidly and the clin. utility of the rifamycin class is typically limited to antibiotic combinations to minimize the development of resistance. To develop a better therapy against persistent bacterial infections, a series of rifamycin based bifunctional mols. were designed, synthesized, and evaluated with the goal to identify a dual-acting drug that maintains the potent activity of rifamycins against persistent pathogens and at the same time minimize the development of rifamycin resistance. TNP-2092 was identified as a drug candidate and is currently in an early stage of clin. development for the treatment of prosthetic joint infections.
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Gupta, V. and Datta, P. (2019) Next-Generation Strategy for Treating Drug Resistant Bacteria: Antibiotic Hybrids. Indian J. Med. Res. 149, 97– 106, DOI: 10.4103/ijmr.IJMR_755_18
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Next-generation strategy for treating drug resistant bacteria: Antibiotic hybrids
Gupta, Varsha; Datta, Priya
Indian Journal of Medical Research (2019), 149 (2), 97-106CODEN: IMIREV ISSN:. (Medknow Publications)
A review. Resistance against nearly all antibiotics used clin. have been documented in bacteria. There is an ever-increasing danger caused by multidrug-resistant Gram-neg. bacteria in both hospital and community settings. In Gram-neg. bacteria, intrinsic resistance to currently available antibiotics is mainly due to overexpressed efflux pumps which are constitutively present and also presence of protective outer membrane. Combination therapy, i.e., use of two or more antibiotics, was thought to be an effective strategy because it took advantage of the additive effects of multiple antimicrobial mechanisms, lower risk of resistance development and lower mortality and improved clin. outcome. However, none of the benefits were seen in in vivo studies. Antibiotic hybrids are being used to challenge the growing drug resistance threat and increase the usefulness of current antibiotic arsenal. Antibiotic hybrids are synthetic constructs of two mols. which are covalently linked. These could be two antibiotics or antibiotic with an adjuvant (efflux pump inhibitor, siderophore, etc.) which increases the access of the antibiotics to the target. The concepts, developments and challenges in the future use of antibiotic hybrids are discussed here. Majority of the studies have been conducted on fluoroquinolones and aminoglycosides mols. The antibiotic tobramycin has the property to enhance the action of antimicrobial agents against which the multidrug-resistant Gram-neg. bacteria were earlier resistant, and thus potentiating the action of legacy antibiotics. Antibiotic hybrids may have a role as the silver bullet in Gram-neg. bacteria to overcome drug resistance as well as extend the spectrum of existing antibiotics.
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Endres, B. T., Basseres, E., Alam, M. J., and Garey, K. W. (2017) Cadazolid for the Treatment of Clostridium Difficile. Expert Opin. Invest. Drugs 26, 509– 514, DOI: 10.1080/13543784.2017.1304538
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Cadazolid for the treatment of Clostridium difficile
Endres, Bradley T.; Basseres, Eugenie; Alam, M. Jahangir; Garey, Kevin W.
Expert Opinion on Investigational Drugs (2017), 26 (4), 509-514CODEN: EOIDER; ISSN:1354-3784. (Taylor & Francis Ltd.)
Antibiotic development goals for CDI include potent antimicrobial effect against C. difficile, limited killing of host microbiota, potential effect on spores, and ability to interfere with toxin prodn. Cadazolid, a novel, non-absorbable hybrid antibiotic has many of these criteria. In phase I and II clin. trials, cadazolid was shown to be safe, well tolerated, and efficacious positioning itself as a potential future viable therapeutic option for CDI. This review provides an in-depth evaluation of the chem., microbiol., pharmacodynamics, pharmacokinetics, and clin. trial results for cadazolid. Clin. therapeutic outcomes are compared between cadazolid, fidaxomicin, and surotomycin. Preclin. and early clin. studies demonstrated that cadazolid has unique properties that will likely be valuable to treat CDI and reduce recurrent infection. With compelling phase II clin. results, results from the ongoing phase III trial will better define the role of cadazolid for treating CDI in the future.
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Stryjewski, M. E., Potgieter, P. D., Li, Y.-P., Barriere, S. L., Churukian, A., Kingsley, J., and Corey, G. R. (2012) TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections. Antimicrob. Agents Chemother. 56, 5476– 5483, DOI: 10.1128/AAC.00712-12
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TD-1792 versus vancomycin for treatment of complicated skin and skin structure infections
Stryjewski, Martin E.; Potgieter, Peter D.; Li, Yu-Ping; Barriere, Steven L.; Churukian, Allan; Kingsley, Jeff; Corey, G. Ralph
Antimicrobial Agents and Chemotherapy (2012), 56 (11), 5476-5483CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
TD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-pos. pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-pos. organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body wt. i.v. [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clin. success at the test-of-cure evaluation were similar in all anal. populations. Among 170 clin. evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, resp. (95% confidence interval [CI] of -7.9 to 9.7 for the difference). In microbiol. evaluable patients with methicillin-resistant Staphylococcus aureus at baseline (n = 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiol. eradication of Gram-pos. pathogens (n = 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, resp. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, resp. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clin. development of TD-1792 in patients with Gram-pos. infection.
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Webb, E. (accessed 2020-03-10) FDA grants QIDP and Fast Track Designations to MCB3837, Morphochem’s novel intravenous antibacterial to treat C. difficile infections, https://www.tvm-lifescience.com/fda-grants-qidp-fast-track-designations-mcb3837-morphochems-novel-intravenous-antibacterial-treat-c-difficile-infections/.
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Parkes, A. L. and Yule, I. A. (2016) Hybrid Antibiotics - Clinical Progress and Novel Designs. Expert Opin. Drug Discovery 11, 665– 680, DOI: 10.1080/17460441.2016.1187597
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Hybrid antibiotics - clinical progress and novel designs
Parkes, Alastair L.; Yule, Ian A.
Expert Opinion on Drug Discovery (2016), 11 (7), 665-680CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)
A review. There is a growing need for new antibacterial agents, but success in development of antibiotics in recent years has been limited. This has led researchers to investigate novel approaches to finding compds. that are effective against multi-drug resistant bacteria, and that delay onset of resistance. One such strategy has been to link antibiotics to produce hybrids designed to overcome resistance mechanisms. The concept of dual-acting hybrid antibiotics was introduced and reviewed in this journal in 2010. In the present review the authors sought to discover how clin. candidates described had progressed, and to examine how the field has developed. In three sections the authors cover the clin. progress of hybrid antibiotics, novel agents produced from hybridization of two or more small-mol. antibiotics, and novel agents produced from hybridization of antibiotics with small-mols. that have complementary activity. Many key questions regarding dual-acting hybrid antibiotics remain to be answered, and the proposed benefits of this approach are yet to be demonstrated. While Cadazolid in particular continues to progress in the clinic, suggesting that there is promise in hybridization through covalent linkage, it may be that properties other than antibacterial activity are key when choosing a partner mol.
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Locher, H. H., Seiler, P., Chen, X., Schroeder, S., Pfaff, P., Enderlin, M., Klenk, A., Fournier, E., Hubschwerlen, C., Ritz, D., Kelly, C. P., and Keck, W. (2014) In Vitro and in Vivo Antibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium Difficile Infections. Antimicrob. Agents Chemother. 58, 892– 900, DOI: 10.1128/AAC.01830-13
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In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections
Locher, Hans H.; Seiler, Peter; Chen, Xinhua; Schroeder, Susanne; Pfaff, Philippe; Enderlin, Michel; Klenk, Axel; Fournier, Elvire; Hubschwerlen, Christian; Ritz, Daniel; Kelly, Ciaran P.; Keck, Wolfgang
Antimicrobial Agents and Chemotherapy (2014), 58 (2), 892-900, 10 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Clostridium difficile is a leading cause of health care-assocd. diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-assocd. diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clin. development for treatment of CDAD. Here, the authors report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 μg/mL, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics expts., cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concns. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further studies of cadazolid for the treatment of CDAD.
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Locher, H. H., Caspers, P., Bruyère, T., Schroeder, S., Pfaff, P., Knezevic, A., Keck, W., and Ritz, D. (2014) Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium Difficile Infections. Antimicrob. Agents Chemother. 58, 901– 908, DOI: 10.1128/AAC.01831-13
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Investigations of the mode of action and resistance development of cadazolid, a new antibiotic for treatment of Clostridium difficile infections
Locher, Hans H.; Caspers, Patrick; Bruyere, Thierry; Schroeder, Susanne; Pfaff, Philippe; Knezevic, Andreja; Keck, Wolfgang; Ritz, Daniel
Antimicrobial Agents and Chemotherapy (2014), 58 (2), 901-908, 9 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Cadazolid is a new oxazolidinone-type antibiotic currently in clin. development for the treatment of Clostridium difficile-assocd. diarrhea. Here, the authors report studies on the mode of action and the propensity for spontaneous resistance development in C. difficile strains. Macromol. labeling expts. indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also obsd., albeit only at substantially higher concns. of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using exts. from different C. difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10-10 at 2× to 4× the MIC), and in multiple-passage expts. (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was obsd., as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.
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Leuthner, K. D., Vidaillac, C., Cheung, C. M., and Rybak, M. J. (2010) In Vitro Activity of the New Multivalent Glycopeptide-Cephalosporin Antibiotic TD-1792 against Vancomycin-Nonsusceptible Staphylococcus Isolates. Antimicrob. Agents Chemother. 54, 3799– 3803, DOI: 10.1128/AAC.00452-10
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In vitro activity of the new multivalent glycopeptide-cephalosporin antibiotic TD-1792 against vancomycin-nonsusceptible Staphylococcus isolates
Leuthner, Kimberly D.; Vidaillac, Celine; Cheung, Chrissy M.; Rybak, Michael J.
Antimicrobial Agents and Chemotherapy (2010), 54 (9), 3799-3803CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
TD-1792 is a glycopeptide-cephalosporin heterodimer antibiotic with activity against a broad spectrum of Gram-pos. pathogens that includes methicillin-susceptible and -resistant Staphylococcus aureus. The objective of the present study was to evaluate the in vitro activity of TD-1792 against a collection of clin. isolates of vancomycin-intermediate Staphylococcus spp. (VISS), heteroresistant VISS (hVISS), and vancomycin-resistant S. aureus (VRSA). The TD-1792, vancomycin, daptomycin, linezolid, and quinupristin-dalfopristin MICs and min. bactericidal concns. (MBCs) were detd. for 50 VISS/hVISS isolates and 3 VRSA isolates. Time-kill expts. (TKs) were then performed over 24 h with two vancomycin-intermediate S. aureus strains and two VRSA strains, using each agent at multiples of the MIC. TD-1792 and daptomycin were also evaluated in the presence and absence of 50% human serum to det. the effects of the proteins on their activities. Most of the VISS/hVISS isolates were susceptible to all agents except vancomycin. TD-1792 exhibited the lowest MIC values (MIC90 = 0.125 μg/mL), followed by quinupristin-dalfopristin and daptomycin (MIC90 = 1 μg/mL) and then linezolid (MIC90 = 2 μg/mL). The presence of serum resulted in a 2- to 8-fold increase in the TD-1792 and daptomycin MIC values. In TKs, QD demonstrated bactericidal activity at multiples of the MIC that simulated therapeutic levels, whereas linezolid was only bacteriostatic. Both TD-1792 and daptomycin demonstrated rapid bactericidal activities against all isolates tested. The presence of proteins had only a minimal impact on the activity of TD-1792 in TKs. TD-1792 exhibited significant in vitro activity against multidrug-resistant Staphylococcus isolates and represents a promising candidate for the treatment of infections caused by Gram-pos. organisms.
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Blais, J., Lewis, S. R., Krause, K. M., and Benton, B. M. (2012) Antistaphylococcal Activity of TD-1792, a Multivalent Glycopeptide-Cephalosporin Antibiotic. Antimicrob. Agents Chemother. 56, 1584– 1587, DOI: 10.1128/AAC.05532-11
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Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic
Blais, Johanne; Lewis, Stacey R.; Krause, Kevin M.; Benton, Bret M.
Antimicrobial Agents and Chemotherapy (2012), 56 (3), 1584-1587CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
TD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-pos. bacteria. The in vitro activity of TD-1792 was tested against 527 Staphylococcus aureus isolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptible S. aureus (MIC90, 0.015 μg/mL), methicillin-resistant S. aureus, and heterogeneous vancomycin-intermediate S. aureus (MIC90, 0.03 μg/mL). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concns. of ≤0.12 μg/mL. A postantibiotic effect of >2 h was obsd. after exposure to TD-1792.
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Pokrovskaya, V. and Baasov, T. (2010) Dual-Acting Hybrid Antibiotics: A Promising Strategy to Combat Bacterial Resistance. Expert Opin. Drug Discovery 5, 883– 902, DOI: 10.1517/17460441.2010.508069
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Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance
Pokrovskaya, Varvara; Baasov, Timor
Expert Opinion on Drug Discovery (2010), 5 (9), 883-902CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)
A review. Importance of the field: The emerging and sustained resistance to currently available antibiotics and the poor pipeline of new antibacterials urgently call for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell covalently linked into one mol. The possible benefits include: (i) activity against drug-resistant bacteria, (ii) expanded spectrum of activity and (iii) reduced potential for generating bacterial resistance.Areas covered in this review: In this article, we detail the recent activity in the design and development of dual-action hybrid drugs with a non-cleavable linker. We explore newly developed synergistic and antagonistic hybrid compds. with emphases on their potential to reduce resistance development.What the reader will gain: Recently developed synergistic and antagonistic antibacterial drug-drug interactions and the impact of such interactions on the evolution of antibiotic drug resistance are described. Addnl., we discuss the implications of the latter observations on the development of hybrid antibiotics with the emphases on whether their synergistic or antagonistic effect will be more efficient at forestalling/reducing the development of new resistances.Take home message: The approach of dual-acting hybrid antibiotics holds significant current promise in overcoming existing resistance mechanisms, as three of such compds. are entering clin. trials. However, the key challenge in this area should be a broader exptl. demonstration of whether the "synergistic effect" or the "antagonistic effect" of the developed hybrid drug is better at preventing/reducing the evolution of resistance. This fundamental challenge must be overcome before yielding a successful drug.
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Deinove. (accessed 2020-03-10) DNV3837/DNV3681: First-in-class antibiotic candidate, https://www.deinove.com/en/antibiotics/portfolio/dnv3837/dnv3681.
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Deinove. (accessed 2020-03-10) An Exploratory, Open-Label, Oligo-Center Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Intravenous DNV3837 in Subjects With Clostridium Difficile Infection, https://clinicaltrials.gov/ct2/show/NCT03988855?term=DNV3681&draw=2&rank=1.
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Wang, B., Zhao, Q., Yin, W., Yuan, Y., Wang, X., Wang, Y.-H., Wang, H., Ye, W., Chen, S., Guo, H.-L., and Xie, Y. (2018) In-Vitro Characterisation of a Novel Antimicrobial Agent, TNP-2092, against Helicobacter Pylori Clinical Isolates. Swiss Med. Wkly. 148, w14630 DOI: 10.4414/smw.2018.14630
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In-vitro characterisation of a novel antimicrobial agent, TNP-2092, against Helicobacter pylori clinical isolates
Ben, Wang; Zhao, Qiaoyun; Yin, Wenzhu; Ying, Yuan; Wang, Xiaomei; Wang, You-Hua; Hui, Wang; Wen, Ye; Chen, Shuping; Guo, Hai-Long; Yong, Xie
Swiss Medical Weekly (2018), 148 (July), 14630CODEN: SMWWAI; ISSN:1424-7860. (EMH Swiss Medical Publishers Ltd.)
BACKGROUND AND OBJECTIVES: TNP-2092 is a novel dual-action lead compd. consisting of rifamycin SV and 4H-4-oxo-quinolizine pharmacophores, with a broad spectrum of antibacterial activities. This compd. is currently in the early stage of clin. development for Helicobacter pylori infection. The aim of the present study was to det. the antibacterial activity of TNP-2092 against H. pylori isolated from primary patients. METHODS: A total of 100 H. pylori clin. isolates from primary patients were selected. The min. inhibitory concns. (MICs) for clarithromycin, levofloxacin, rifampin and TNP-2092 were detd. using an agar diln. method. A time-kill study was performed with different concns. of TNP-2092 relevant to MIC against H. pylori ATCC strain 43504 for up to 24 h. The timekill study with drug concns. of 0-4 × MIC was also used to det. the antibacterial activity of TNP-2092 against H. pylori under different pH conditions (pH 4-7). RESULTS: The primary resistance percentages to clarithromycin, levofloxacin, rifampin and TNP-2092 were 13, 18, 1 and 1%, resp. TNP-2092 killing kinetics were both concn. and time dependent. The effectiveness of TNP-2092 against H. pylori was gradually reduced with a decrease in pH. CONCLUSIONS: TNP-2092 is highly active against H. pylori and against strains resistant to clarithromycin or levofloxacin. Its antibacterial activity is both concentrationand time-dependent.The antibacterial activity of TNP-2092 appears to be pH-dependent and is more active under neutral pH. TNP-2092 represents a promising new therapy for the treatment of H. pylori infection in primary patients.
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Burrows, L. L. (2018) The Therapeutic Pipeline for Pseudomonas Aeruginosa Infections. ACS Infect. Dis. 4, 1041– 1047, DOI: 10.1021/acsinfecdis.8b00112
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The Therapeutic Pipeline for Pseudomonas aeruginosa Infections
Burrows, Lori L.
ACS Infectious Diseases (2018), 4 (7), 1041-1047CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
Pseudomonas aeruginosa is a Gram-neg. opportunistic pathogen, designated by the World Health Organization as a crit. priority for development of new therapeutics due to high levels of intrinsic and acquired antibiotic resistance. Other challenges include its versatility (it can persist in the environment and most strains are capable of causing disease in compromised hosts), robust efflux mechanisms that limit drug penetration, and the propensity to form antimicrobial-tolerant biofilms. Novel therapeutics in development to prevent or treat P. aeruginosa infections include vaccines, biologics such as antimicrobial peptides and therapeutic antibodies, virulence inhibitors, antimicrobials with novel targets, antibody-drug conjugates, resistance inhibitor-antibiotic or antibiotic-potentiator combinations, and bacteriophages or phage-derived lysins.
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Luther, A., Urfer, M., Zahn, M., Muller, M., Wang, S.-Y., Mondal, M., Vitale, A., Hartmann, J.-B., Sharpe, T., Monte, F. Lo (2019) Chimeric Peptidomimetic Antibiotics against Gram-Negative Bacteria. Nature 576, 452– 458, DOI: 10.1038/s41586-019-1665-6
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Chimeric peptidomimetic antibiotics against Gram-negative bacteria
Luther, Anatol; Urfer, Matthias; Zahn, Michael; Muller, Maik; Wang, Shuang-Yan; Mondal, Milon; Vitale, Alessandra; Hartmann, Jean-Baptiste; Sharpe, Timothy; Monte, Fabio Lo; Kocherla, Harsha; Cline, Elizabeth; Pessi, Gabriella; Rath, Parthasarathi; Modaresi, Seyed Majed; Chiquet, Petra; Stiegeler, Sarah; Verbree, Carolin; Remus, Tobias; Schmitt, Michel; Kolopp, Caroline; Westwood, Marie-Anne; Desjonqueres, Nicolas; Brabet, Emile; Hell, Sophie; LePoupon, Karen; Vermeulen, Annie; Jaisson, Regis; Rithie, Virginie; Upert, Gregory; Lederer, Alexander; Zbinden, Peter; Wach, Achim; Moehle, Kerstin; Zerbe, Katja; Locher, Hans H.; Bernardini, Francesca; Dale, Glenn E.; Eberl, Leo; Wollscheid, Bernd; Hiller, Sebastian; Robinson, John A.; Obrecht, Daniel
Nature (London, United Kingdom) (2019), 576 (7787), 452-458CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
There is an urgent need for new antibiotics against Gram-neg. pathogens that are resistant to carbapenem and 3rd-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. We describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-neg. bacteria. Extensively optimized derivs. show potent activity against multidrug-resistant pathogens, including all of the Gram-neg. members of the ESKAPE pathogens. These derivs. also show favorable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclin. toxicol. studies that, if successful, will allow progress into clin. studies that have the potential to address life-threatening infections by the Gram-neg. pathogens, and thus to resolve a considerable unmet medical need.
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Zhu, Y. I. and Stiller, M. J. (2001) Dapsone and Sulfones in Dermatology: Overview and Update. J. Am. Acad. Dermatol. 45, 420– 434, DOI: 10.1067/mjd.2001.114733
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Dapsone and sulfones in dermatology: overview and update
Zhu Y I; Stiller M J
Journal of the American Academy of Dermatology (2001), 45 (3), 420-34 ISSN:0190-9622.
In their 60-year history, dapsone and the sulfones have been used as both antibacterial and anti-inflammatory agents. Dapsone has been used successfully to treat a range of dermatologic disorders, most successfully those characterized by abnormal neutrophil and eosinophil accumulation. This article reviews and updates the chemistry, pharmacokinetics, clinical application, mechanism of action, adverse effects, and drug interactions of dapsone and the sulfones in dermatology.
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Trivedi, H. D., Lizaola, B., Tapper, E. B., and Bonder, A. (2017) Management of Pruritus in Primary Biliary Cholangitis: A Narrative Review. Am. J. Med. 130, 744.e1– 744.e7, DOI: 10.1016/j.amjmed.2017.01.037
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Nakano, T., Hiramatsu, K., Kishi, K., Hirata, N., Kadota, J.-I., and Nasu, M. (2003) Clindamycin Modulates Inflammatory-Cytokine Induction in Lipopolysaccharide-Stimulated Mouse Peritoneal Macrophages. Antimicrob. Agents Chemother. 47, 363– 367, DOI: 10.1128/AAC.47.1.363-367.2003
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Clindamycin modulates inflammatory-cytokine induction in lipopolysaccharide-stimulated mouse peritoneal macrophages
Nakano, Tetsuji; Hiramatsu, Kazufumi; Kishi, Kenji; Hirata, Norio; Kadota, Jun-Ichi; Nasu, Masaru
Antimicrobial Agents and Chemotherapy (2003), 47 (1), 363-367CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
The authors investigated the mechanism by which clindamycin (CLI) modulates cytokine induction after lipopolysaccharide (LPS) stimulation. Although CLI decreased the intracellular expression levels of tumor necrosis factor α and interleukin 1β (IL-1β) and increased IL-6 expression in macrophages, cytokine mRNA expression levels were similar in CLI-treated and untreated groups. Apparently, CLI modulates cytokine prodn. in LPS-stimulated macrophages.
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van Rensburg, C. E., Gatner, E. M., Imkamp, F. M., and Anderson, R. (1982) Effects of Clofazimine Alone or Combined with Dapsone on Neutrophil and Lymphocyte Functions in Normal Individuals and Patients with Lepromatous Leprosy. Antimicrob. Agents Chemother. 21, 693– 697, DOI: 10.1128/AAC.21.5.693
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Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy
Van Rensburg, C. E. J.; Gatner, E. M. S.; Imkamp, F. M. J. H.; Anderson, R.
Antimicrobial Agents and Chemotherapy (1982), 21 (5), 693-7CODEN: AMACCQ; ISSN:0066-4804.
The effects of clofazimine (I) [2030-63-9] on neutrophil activities such as random motility, migration to the leukoattractants endotoxin-activated serum and N-formyl-L-Met-L-Leu-L-Phe [59880-97-6], phagocytosis of Candida albicans, postphagocytic hexose-monophosphate shunt activity, and myeloperoxidase-mediated iodination and the effects of clofazimine on lymphocyte transformation by mitogens were assessed in vitro and after ingestion of the drug by normal individuals and patients with lepromatous leprosy. For in vitro studies, the concn. range of the drug investigated was 10-6-10-2M. For in vivo studies, subjects ingested 200 mg clofazimine daily for 5 days. At 5 × 10-6M-5 × 10-3M, clofazimine caused a progressive concn.-dependent inhibition of neutrophil motility without detectable effects on phagocytosis, postphagocytic hexose-monophosphate shunt activity, or myeloperoxidase-mediated iodination. Over the same concn. range, clofazimine inhibited lymphocyte transformation. The inhibitory effect on neutrophil motility was assocd. with a spontaneous stimulation of oxidative metab. and could be prevented by coincubation of dapsone [80-08-0] with clofazimine. After ingestion of clofazimine responsiveness of lymphocytes to mitogens was decreased in normal volunteers and leprosy patients; neutrophil motility in normal individuals was likewise inhibited.
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Gatner, E. M., Anderson, R., van Remsburg, C. E., and Imkamp, F. M. (1982) The in Vitro and in Vivo Effects of Clofazimine on the Motility of Neutrophils and Transformation of Lymphocytes from Normal Individuals. Lepr. Rev. 53, 85– 90, DOI: 10.5935/0305-7518.19820010
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The in vitro and in vivo effects of clofazimine on the motility of neutrophils and transformation of lymphocytes from normal individuals
Gatner, E. M. S.; Anderson, R.; Van Rensburg, C. E.; Imkamp, Florentine M. J. H.
Leprosy Review (1982), 53 (2), 85-90CODEN: LEREAA; ISSN:0305-7518.
clofazimine (I) [2030-63-9] caused a progressive dose-dependent inhibition of neutrophil motility and of lymphocyte transformation in vitro. Ingestion of the drug by normal volunteers was accompanied by decreased neutrophil motility and lymphocyte transformation to mitogens. Apparently the anti-inflammatory properties of clofazimine are related to inhibition of these cellular immune functions.
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Zimmermann, P., Ziesenitz, V. C., Curtis, N., and Ritz, N. (2018) The Immunomodulatory Effects of Macrolides—A Systematic Review of the Underlying Mechanisms. Front. Immunol. 9, 302, DOI: 10.3389/fimmu.2018.00302
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The immunomodulatory effects of macrolides-a systematic review of the underlying mechanisms
Zimmermann, Petra; Ziesenitz, Victoria C.; Curtis, Nigel; Ritz, Nicole
Frontiers in Immunology (2018), 9 (), 302/1-302/14CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
Background: The mechanisms underlying the non-antimicrobial immunomodulatory properties of macrolides are not well understood. Objectives: To systematically review the evidence for the immunomodulatory properties of macrolides in humans and to describe the underlying mechanism and extent of their influence on the innate and adaptive immune system. methods: A systematic literature search was done in MEDLINE using the OVID interface from 1946 to Dec. 2016 according to the preferred reporting items for systematic reviews and meta-anal. (PRISMA). Original articles investigating the influence of four macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin) on immuno-logical markers in humans were included. Results: We identified 22 randomized, controlled trials, 16 prospective cohort studies, and 8 case-control studies investigating 47 different immunol. markers (186 mea-surements) in 1,834 participants. The most frequently reported outcomes were a decrease in the no. of neutrophils, and the concns. of neutrophil elastase, interleukin (IL)-8, IL-6, IL-1beta, tumor necrosis factor (TNF)-alpha, eosinophilic cationic protein, and matrix metalloproteinase 9. Inhibition of neutrophil function was reported more frequently than eosinophil function. A decrease in T helper (Th) 2 cells cytokines (IL-4, IL-5, IL-6) was reported more frequently than a decrease in Th1 cytokines (IL-2, INF-gamma). conclusion: Macrolides influence a broad range of immunol. mechanisms result-ing in immunomodulatory effects. To optimize the treatment of chronic inflammatory diseases by macrolides, further studies are necessary, particularly comparing different macrolides and dose effect relationships.
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Pasquale, T. R. and Tan, J. S. (2005) Nonantimicrobial Effects of Antibacterial Agents. Clin. Infect. Dis. 40, 127– 135, DOI: 10.1086/426545
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Nonantimicrobial effects of antibacterial agents
Pasquale, Timothy R.; Tan, James S.
Clinical Infectious Diseases (2005), 40 (1), 127-135CODEN: CIDIEL; ISSN:1058-4838. (University of Chicago Press)
A review. One of the major advances in modern medicine was the development of antimicrobial chemotherapy. However, many antibacterial agents have unexpected or undesirable nonantimicrobial effects on humans. Microbes and man share many essentials of life, including DNA, ATP, and other biochem. pathways. Hence, some of these nonanti- microbial effects may also turn out to be pharmacol. useful. Oral hypoglycemic agents (i.e., sulfonylureas) and a certain diuretic agent (acetazolamide) are derivs. of sulfonamides. Erythromycin has been used clin. for its stimulatory effect on gastrointestinal motility. Macrolides, lincosamides, and tetracyclines have been known for their immunomodulatory effects. A tetracycline has been used to treat the syndrome of inappropriate antidiuretic hormone. Aminoglycosides may influence mucus prodn. in patients with cystic fibrosis. Other antimicrobials may have side effects that are not therapeutically useful, such as osmotic diuresis with high-dose β-lactam administration, neuromuscular blockade of aminoglycosides, dysglycemia of fluoroquinolones, and serotonin syndrome with oxazolidinones.
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Tauber, S. C. and Nau, R. (2008) Immunomodulatory Properties of Antibiotics. Curr. Mol. Pharmacol. 1, 68– 79, DOI: 10.2174/1874467210801010068
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Immunomodulatory properties of antibiotics
Tauber, S. C.; Nau, R.
Current Molecular Pharmacology (2008), 1 (1), 68-79CODEN: CMPUB6; ISSN:1874-4672. (Bentham Science Publishers Ltd.)
A review. There is growing evidence that certain antibiotics exert their beneficial effects not only by killing or inhibiting the growth of bacterial pathogens but also indirectly by immunomodulation. This review aims at giving an overview of the immunomodulatory properties of antibiotics in different diseases: The antiinflammatory properties of macrolides in chronic inflammatory pulmonary disorders were recognized more than 15 years ago and have been well documented in the last decade. Recent data suggest that several antibiotics such as tetracyclines and cephalosporins may have a beneficial immunomodulatory or neuroprotective effect on neuroimmunol. and neurodegenerative diseases including multiple sclerosis and amyotrophic lateral sclerosis. Moreover, the non-bacteriolytic but bactericidal antibiotics rifampicin, clindamycin and aminoglycosides kill bacteria without releasing high quantities of proinflammatory cell wall components. The use of bactericidal, non-bacteriolytic protein synthesis inhibitors reduces mortality and long-term sequelae in exptl. bacterial sepsis, plague and meningitis. Clin., macrolides have been well established as an adjunctive treatment to β-lactam antibiotics in pulmonary diseases. For other indications, appropriate clin. trials are necessary before using the immunomodulatory properties of antibiotics in clin. practice.
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Ye, Y., Xia, Z., Zhang, D., Sheng, Z., Zhang, P., Zhu, H., Xu, N., and Liang, S. (2019) Multifunctional Pharmaceutical Effects of the Antibiotic Daptomycin. BioMed Res. Int. 2019, 8609218, DOI: 10.1155/2019/8609218
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Multifunctional Pharmaceutical Effects of the Antibiotic Daptomycin
Ye Yang; Zhang Dan; Sheng Zenghua; Xu Ningzhi; Liang Shufang; Xia Zijing; Zhang Peng; Zhu Hongxia; Xu Ningzhi
BioMed research international (2019), 2019 (), 8609218 ISSN:.
Daptomycin (DAP), a cyclic lipopeptide produced by Streptomyces roseosporus, is a novel antibiotic to clinically treat various Gram-positive pathogenic bacteria-induced infections. Although DAP has a strong broad-spectrum bactericidal effect, recently rare bacterial antibiotic resistance against DAP gradually arises. The review is to summarize the normal indications of DAP, its off-label usage against several clinical pathogen infections, the unique antibacterial mechanisms of DAP, and the combination of antibiotic therapies for highly DAP-resistant pathogens. More noticeably, rising evidences demonstrate that DAP has new potential activity of anticancer and immunomodulatory effects. So far the multifunctional pharmaceutical effects of DAP deserve to be further explored for future clinical applications.
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Jorgensen, S. C. J., Zasowski, E. J., Trinh, T. D., Lagnf, A. M., Bhatia, S., Sabagha, N., Abdul-Mutakabbir, J. C., Alosaimy, S., Mynatt, R. P., Davis, S. L., and Rybak, M. J. (2019) Daptomycin plus Beta-Lactam Combination Therapy for Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections: A Retrospective, Comparative Cohort Study. Clin. Infect. Dis. ciz746 DOI: 10.1093/cid/ciz746
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146
Meletiadis, J., Petraitis, V., Petraitiene, R., Lin, P., Stergiopoulou, T., Kelaher, A. M., Sein, T., Schaufele, R. L., Bacher, J., and Walsh, T. J. (2006) Triazole-Polyene Antagonism in Experimental Invasive Pulmonary Aspergillosis: In Vitro and in Vivo Correlation. J. Infect. Dis. 194, 1008– 1018, DOI: 10.1086/506617
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Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo correlation
Meletiadis, Joseph; Petraitis, Vidmantas; Petraitiene, Ruta; Lin, Pengxin; Stergiopoulou, Theodouli; Kelaher, Amy M.; Sein, Tin; Schaufele, Robert L.; Bacher, John; Walsh, Thomas J.
Journal of Infectious Diseases (2006), 194 (7), 1008-1018CODEN: JIDIAQ; ISSN:0022-1899. (University of Chicago Press)
Combination antifungal therapy is increasingly used in the treatment of invasive aspergillosis. Whether the interaction between amphotericin B and triazoles is antagonistic against invasive aspergillosis is a controversial issue that is not likely to be resolved through a randomized clin. trial. Here, we found both in vitro and in vivo antagonism between liposomal amphotericin B and ravuconazole in simultaneous treatment of exptl. invasive pulmonary aspergillosis in persistently neutropenic rabbits. Bliss independence-based drug-interaction modeling showed significant antagonism in vitro and in vivo, with the obsd. drug effects being 20%-69% lower than would be expected if the drugs were acting independently. These in vitro and in vivo findings of antagonism were consistent with the findings from Loewe additivity-based drug-interaction modeling. No pharmacokinetic interaction was found. The combination of a triazole and polyene may be antagonistic in the treatment of invasive pulmonary aspergillosis.
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Gonzalez-Bello, C. (2017) Antibiotic Adjuvants - A Strategy to Unlock Bacterial Resistance to Antibiotics. Bioorg. Med. Chem. Lett. 27, 4221– 4228, DOI: 10.1016/j.bmcl.2017.08.027
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Antibiotic adjuvants - A strategy to unlock bacterial resistance to antibiotics
Gonzalez-Bello, Concepcion
Bioorganic & Medicinal Chemistry Letters (2017), 27 (18), 4221-4228CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the no. of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has spread worldwide. To unlock this problem, the use of an 'antibiotic adjuvant' in combination with an antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those compds. that are already in clin. development, namely β-lactamase inhibitors.
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Kwapong, A. A., Stapleton, P., and Gibbons, S. (2019) Inhibiting Plasmid Mobility: The Effect of Isothiocyanates on Bacterial Conjugation. Int. J. Antimicrob. Agents 53, 629– 636, DOI: 10.1016/j.ijantimicag.2019.01.011
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Inhibiting plasmid mobility: The effect of isothiocyanates on bacterial conjugation
Kwapong, Awo Afi; Stapleton, Paul; Gibbons, Simon
International Journal of Antimicrobial Agents (2019), 53 (5), 629-636CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
Bacterial conjugation is the main mechanism for the transfer of multiple antimicrobial resistance genes among pathogenic microorganisms. This process may be controlled by compds. that inhibit bacterial conjugation. The effects of allyl isothiocyanate, L-sulforaphane, benzyl isothiocyanate, phenylethyl isothiocyanate, and 4-methoxyphenyl isothiocyanate on the conjugation of broad-host-range plasmids harboring various antimicrobial resistance genes in Escherichia coli were investigated, namely plasmids pKM101 (IncN), TP114 (IncI2), pUB307 (IncP), and the low-copy-no. plasmid R7K (IncW). Benzyl isothiocyanate (32 mg/L) significantly reduced conjugal transfer of pKM101, TP114, and pUB307 to 0.3%, 10.7%, and 6.5%, resp.; L-sulforaphane (16 mg/L; transfer frequency 21.5%); and 4-methoxyphenyl isothiocyanate (100 mg/L; transfer frequency 5.2%) were the only compds. showing anti-conjugal specificity by actively reducing the transfer of R7K and pUB307, resp.
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Zhao, W. H., Hu, Z. Q., Okubo, S., Hara, Y., and Shimamura, T. (2001) Mechanism of Synergy between Epigallocatechin Gallate and Beta-Lactams against Methicillin-Resistant Staphylococcus Aureus. Antimicrob. Agents Chemother. 45, 1737– 1742, DOI: 10.1128/AAC.45.6.1737-1742.2001
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Mechanism of synergy between epigallocatechin gallate and β-lactams against methicillin-resistant Staphylococcus aureus
Zhao, Wei-Hua; Hu, Zhi-Qing; Okubo, Sachie; Hara, Yukihiko; Shimamura, Tadakatsu
Antimicrobial Agents and Chemotherapy (2001), 45 (6), 1737-1742CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
Compared to MICs (>800 μg/mL) of (-)-epigallocatechin gallate (I) against Escherichia coli, MICs of I against methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA) were ≤100 μg/mL. Furthermore, <25 μg I/mL obviously reversed the high level resistance of MRSA to all types of tested β-lactams, including benzylpenicillin, oxacillin, methicillin, ampicillin, and cephalexin. I also induced a supersusceptibility to β-lactams in MSSA which does not express mecA, encoding penicillin-binding protein 2' (PBP2'). The fractional inhibitory concn. (FIC) indexes of the tested β-lactams against 25 isolates of MRSA were 0.126-0.625 in combination with 6.25, 12.5, or 25 μg I/mL. However, no synergism was obsd. between I and ampicillin against E. coli. I largely reduced the tolerance of MRSA and MSSA to high ionic strength and low osmotic pressure in their external atm., indicating damage of the cell wall. Unlike dextran and lipopolysaccharide, peptidoglycan from S. aureus blocked both the antibacterial activity of I and the synergism between I and oxacillin, suggesting a direct binding of I with peptidoglycan on the cell wall. I showed a synergistic effect with DL-cycloserine (an inhibitor of cell wall synthesis unrelated to PBP2') but additive or indifferent effect with inhibitors of protein and nuclear acid synthesis. I did not suppress either PBP2' mRNA expression or PBP2' prodn., as confirmed by reverse transcription-PCR and a semiquant. PBP2' latex agglutination assay, indicating an irrelevance between the synergy and PBP2' prodn. In summary, both I and β-lactams directly or indirectly attack the same site, peptidoglycan on the cell wall. I synergizes the activity of β-lactams against MRSA owing to interference with the integrity of the cell wall through direct binding to peptidoglycan.
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Rand, K. H. and Houck, H. (2004) Daptomycin Synergy with Rifampicin and Ampicillin against Vancomycin-Resistant Enterococci. J. Antimicrob. Chemother. 53, 530– 532, DOI: 10.1093/jac/dkh104
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Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci
Rand, Kenneth H.; Houck, Herbert
Journal of Antimicrobial Chemotherapy (2004), 53 (3), 530-532CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
The authors used a novel screening method to look for synergy between daptomycin and 18 other antibiotics against 19 strains of high-level vancomycin-resistant enterococci (VRE) (vancomycin MIC ≥ 256 mg/L). In this approach, daptomycin was incorporated into Ca2+-supplemented Mueller-Hinton agar at subinhibitory concns., and synergy was screened by comparing test antibiotic Etest MICs on agar with and without daptomycin. A striking redn. in the rifampicin MIC was seen in 11/15 (73.3%) VRE that were resistant to rifampicin, from ≥12 mg/L to a mean ± s.d. of 0.22 ± 0.21 mg/L at daptomycin 0.25 × MIC and 0.85 ± 0.90 mg/L at daptomycin 0.125 × MIC. Synergy was also obsd. for 13/19 (68%) isolates with ampicillin (MIC ≥ 128 mg/L). There was no significant synergy between daptomycin and any other antibiotic by this screening method. If confirmed by further studies, daptomycin with either rifampicin or ampicillin may be useful in the management of infections caused by VRE.
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Paul, T. R., Venter, A., Blaszczak, L. C., Parr, T. R. J., Labischinski, H., and Beveridge, T. J. (1995) Localization of Penicillin-Binding Proteins to the Splitting System of Staphylococcus Aureus Septa by Using a Mercury-Penicillin V Derivative. J. Bacteriol. 177, 3631– 3640, DOI: 10.1128/JB.177.13.3631-3640.1995
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Localization of penicillin-binding proteins to the splitting system of Staphylococcus aureus septa by using a mercury-penicillin V derivative
Paul, Terry R.; Venter, Alexandra; Blaszczak, Larry C.; Parr, Tom R., Jr.; Labischinski, Harald; Beveridge, Terry J.
Journal of Bacteriology (1995), 177 (13), 3631-40CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
Precise localization of penicillin-binding protein (PBP)-antibiotic complexes in a methicillin-sensitive Staphylococcus aureus strain (BB255), its isogenic heterogeneous methicillin-resistant transductant (BB270), and a homogeneous methicillin-resistant strain (Col) was investigated by high-resoln. electron microscopy. A mercury-penicillin V (Hg-pen V) deriv. was used as a heavy metal-labeled, electron-dense probe for accurately localizing PBPs in situ in single bacterial cells during growth. The most striking feature of thin sections was the presence of an abnormally large (17 to 24 nm in width) splitting system within the thick cross walls or septa of Hg-pen V-treated bacteria of all strains. Untreated control cells possessed a thin, condensed splitting system, 7 to 9 nm in width. A thick splitting system was also distinguishable in unstained thin sections, thereby confirming that the electron contrast of this structure was not attributed to binding of bulky heavy metal stains usually used for electron microscopy. Biochem. analyses demonstrated that Hg-pen V bound to isolated plasma membranes as well as sodium dodecyl sulfate-treated cell walls and that two or more PBPs in each strain bound to this antibiotic. In contrast, the splitting system in penicillin V-treated bacteria was rarely visible after 30 min in the presence of antibiotic. These findings suggest that while most PBPs were assocd. with the plasma membrane, a proportion of PBPs were located within the fabric of the cell wall, in particular, in the splitting system. Inhibition of one or more high-Mr PBPs by β-lactam antibiotics modified the splitting system and cross-wall structure, therefore supporting a role for these PBPs in the synthesis and architectural design of these structures in S. aureus.
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Biebricher, C. K. and Druminski, M. (1980) Inhibition of RNA Polymerase Activity by the Escherichia Coli Protein Biosynthesis Elongation Factor Ts. Proc. Natl. Acad. Sci. U. S. A. 77, 866– 869, DOI: 10.1073/pnas.77.2.866
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Inhibition of RNA polymerase activity by the Escherichia coli protein biosynthesis elongation factor Ts
Biebricher, Christof K.; Druminski, Maria
Proceedings of the National Academy of Sciences of the United States of America (1980), 77 (2), 866-9CODEN: PNASA6; ISSN:0027-8424.
The transcribing activity of DNA-dependent RNA polymerase (EC 2.7.7.6) from E. coli was inhibited in vitro by addn. of prepns. of elongation factor Ts purified to homogeneity. The inhibitory activity of elongation factor Ts on RNA polymerase activity and the enzymic activity of elongation factor Ts showed the same temp. sensitivity. The extent of inhibition was strongly dependent on the template used for transcription. A mechanism for the control of RNA synthesis in vivo based on this inhibition found in vitro is proposed.
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153
Nasher, M. A. and Hay, R. J. (1998) Synergy of Antibiotics against Streptomyces Somaliensis Isolates in Vitro. J. Antimicrob. Chemother. 41, 281– 284, DOI: 10.1093/jac/41.2.281
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153
Synergy of antibiotics against Streptomyces somaliensis isolates in vitro
Nasher, M. A.; Hay, R. J.
Journal of Antimicrobial Chemotherapy (1998), 41 (2), 281-284CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
Eight dual antibiotic combinations were used to investigate possible synergic effects against different isolates of Streptomyces somaliensis. The antibiotic combinations that showed synergic activity against the isolates were, in decreasing order, fusidic acid-rifampicin, erythromycin-penicillin, erythromycin-fusidic acid, rifampicin-sulphamethoxazole, fusidic acid-sulphamethoxazole and erythromycin-rifampicin. Sulphamethoxazole-trimethoprim and rifampicin-trimethoprim combinations were not synergic against any of the S. somaliensis isolates tested.
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Lowe, P. A. and Malcolm, A. D. (1976) Rifampicin Binding as a Probe for Subunit Interactions in Escherchia Coli RNA Polymerase. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 454, 129– 137, DOI: 10.1016/0005-2787(76)90360-9
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154
Rifampicin binding as a probe for subunit interactions in Escherichia coli RNA polymerase
Lowe, Peter A.; Malcolm, Alan D. B.
Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1976), 454 (1), 129-37CODEN: BBNPAS; ISSN:0005-2787.
The binding of the inhibitor rifampicin to RNA polymerase(α2ββ1) and its deficient subunit mixts. was investigated. The ability of β to bind stoichiometric amts. of rifampicin was restored by formation of the α2β subassembly. β,β1α, ββ1, And α2β1 were unable to bind rifampicin. RNA polymerase denatured with 6M guanidine-HCl and dialyzed against a renaturing buffer at 0° (renatured inactive enzyme) bound stoichiometric amts. of rifampicin but lost the ability to bind DNA. Compared with native RNA polymerase renatured inactive enzyme possessed a markedly different tertiary structure as judged by limited proteolysis.
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Lee-Huang, S., Lee, H., and Ochoa, S. (1974) Inhibition of Polypeptide Chain Initiation in Escherichia Coli by Elongation Factor G. Proc. Natl. Acad. Sci. U. S. A. 71, 2928– 2931, DOI: 10.1073/pnas.71.8.2928
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Inhibition of polypeptide chain initiation in Escherichia coli by elongation factor G
Lee-Huang, Sylvia; Lee, Henry; Ochoa, Severo
Proceedings of the National Academy of Sciences of the United States of America (1974), 71 (8), 2928-31CODEN: PNASA6; ISSN:0027-8424.
A specific inhibitor of polypeptide chain initiation from E. coli is rendered ineffective when active aminoacylation of transfer RNA is taking place (Lee-Huang, S., et al., 1973). The inhibitory activity appeared to be a hitherto unrecognized property of the chain elongation factor G. The following hold for prepns. purified for either translocase or inhibitor activity: (1) equal electrophoretic mobility on polyacrylamide gels; (2)equal sp. activities for inhibition of initiation, translocation, and ribosome-dependent, uncoupled GTPase; and (3) similar heat sensitivity of translocase and inhibitor activities in a temp.-sensitive E. coli mutant with an altered elongation factor G. Different sites are apparently involved in translocation and inhibition because the former, but not the latter, is sensitive to p-chloromercuribenzoate and fusidic acid.
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Dinos, G. P., Connell, S. R., Nierhaus, K. H., and Kalpaxis, D. L. (2003) Erythromycin, Roxithromycin, and Clarithromycin: Use of Slow-Binding Kinetics to Compare Their in Vitro Interaction with a Bacterial Ribosomal Complex Active in Peptide Bond Formation. Mol. Pharmacol. 63, 617– 623, DOI: 10.1124/mol.63.3.617
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156
Erythromycin, roxithromycin, and clarithromycin: Use of slow-binding kinetics to compare their in vitro interaction with a bacterial ribosomal complex active in peptide bond formation
Dinos, George P.; Connell, Sean R.; Nierhaus, Knud H.; Kalpaxis, Dimitrios L.
Molecular Pharmacology (2003), 63 (3), 617-623CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)
In a cell-free system derived from Escherichia coli, it is shown that clarithromycin and roxithromycin, like their parent compd. erythromycin, do not inhibit the puromycin reaction (i.e., the peptide bond formation between puromycin and AcPhe-tRNA bound at the P-site of 70S ribosomes programmed with heteropolymeric mRNA). Nevertheless, all three antibiotics compete for binding on the ribosome with tylosin, a 16-membered ring macrolide that behaves as a slow-binding, slowly reversible inhibitor of peptidyltransferase. The mutually exclusive binding of these macrolides to ribosomes is also corroborated by the fact that they protect overlapping sites in domain V of 23S rRNA from chem. modification by di-Me sulfate. From this competition effect, detailed kinetic anal. revealed that roxithromycin or clarithromycin (A), like erythromycin, reacts rapidly with AcPhe-tRNA·MF-mRNA·70S ribosomal complex (C) to form the encounter complex CA which is then slowly isomerized to a more tight complex, termed C*A. MF-mRNA is a heteropolymeric synthetic mRNA used as template in place of poly(U). It is 46-nucleotides long with an AUG codon in the middle, followed by a UUC codon. The value of the overall dissocn. const., K*A, encompassing both steps of macrolide interaction with complex C, is 36 nM for erythromycin, 20 nM for roxithromycin, and 8 nM for clarithromycin. Because the off-rate const. of C*A complex does not significantly differ among the three macrolides, the superiority of clarithromycin as an inhibitor of translation in E. coli cells and many Gram-pos. bacteria may be correlated with its greater rate of assocn. with ribosomes.
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Allen, N. E. and Epp, J. K. (1978) Mechanism of Penicillin-Erythromycin Synergy on Antibiotic-Resistant Staphylococcus Aureus. Antimicrob. Agents Chemother. 13, 849– 853, DOI: 10.1128/AAC.13.5.849
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Mechanism of penicillin-erythromycin synergy on antibiotic-resistant Staphylococcus aureus
Allen, Norris E.; Epp, Janet K.
Antimicrobial Agents and Chemotherapy (1978), 13 (5), 849-53CODEN: AMACCQ; ISSN:0066-4804.
Clin. isolated strains of S. aureus that are inducibly resistant to both erythromycin [114-07-8] and benzylpenicillin [61-33-6] were susceptible to a combination of the 2 antibiotics. The synergistic effect of the combination results from an inhibition of penicillinase [9001-74-5] induction by erythromycin, sparing penicillin and allowing this drug to inhibit growth. When resistance to erythromycin was constitutive rather than inducible, the combination was no longer synergistic.
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Guignard, B., Entenza, J. M., and Moreillon, P. (2005) Beta-Lactams against Methicillin-Resistant Staphylococcus Aureus. Curr. Opin. Pharmacol. 5, 479– 489, DOI: 10.1016/j.coph.2005.06.002
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158
β-lactams against methicillin-resistant Staphylococcus aureus
Guignard, Bertrand; Entenza, Jose M.; Moreillon, Philippe
Current Opinion in Pharmacology (2005), 5 (5), 479-489CODEN: COPUBK; ISSN:1471-4892. (Elsevier Ltd.)
A review. Methicillin-resistant Staphylococcus aureus (MRSA) have developed resistance to virtually all non-exptl. antibiotics. They are intrinsically resistant to β-lactams by virtue of newly acquired low-affinity penicillin-binding protein 2A (PBP2A). Because PBP2A can build the wall when other PBPs are blocked by β-lactams, designing β-lactams capable of blocking this addnl. target should help solve the issue. Older mols. including penicillin G, amoxicillin and ampicillin had relatively good PBP2A affinities, and successfully treated exptl. endocarditis caused by MRSA, provided that the bacterial penicillinase could be inhibited. Newer anti-PBP2A β-lactams with over 10-fold greater PBP2A affinities and low minimal inhibitory concns. were developed, primarily in the cephem and carbapenem classes. They are also very resistant to penicillinase. Most have demonstrated anti-MRSA activity in animal models of infection, and two - the carbapenem CS-023 and the cephalosporin ceftopibrole medocaril - have proceeded to Phase II and Phase III clin. evaluation. Thus, clin. useful anti-MRSA β-lactams are imminent.
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Brandt, C. M., Rouse, M. S., Laue, N. W., Stratton, C. W., Wilson, W. R., and Steckelberg, J. M. (1996) Effective Treatment of Multidrug-Resistant Enterococcal Experimental Endocarditis with Combinations of Cell Wall-Active Agents. J. Infect. Dis. 173, 909– 913, DOI: 10.1093/infdis/173.4.909
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Effective treatment of multidrug-resistant enterococcal experimental endocarditis with combinations of cell wall-active agents
Brandt, Claudia M.; Rouse, Mark S.; Laue, Natasha W.; Stratton, Charles W.; Wilson, Walter R.; Steckelberg, James M.
Journal of Infectious Diseases (1996), 173 (4), 909-13CODEN: JIDIAQ; ISSN:0022-1899. (University of Chicago Press)
The efficacy of treatment with a combination of ampicillin, imipenem, and vancomycin was compared with that of two-drug combinations or monotherapy in a model of exptl. endocarditis using a strain of Enterococcus faecium with high-level resistance to vancomycin and moderate intrinsic resistance to ampicillin and imipenem. In vitro time-kill synergy studies demonstrated bactericidal synergistic activity only for the triple combination. In vivo, monotherapy with vancomycin was not effective. Treatment with either ampicillin or imipenem alone or in combination with vancomycin resulted in <4 log10 redn. in colony-forming units (cfu) per g of vegetation. The combination of ampicillin with imipenem was highly active (an addnl. 5 log10 redn. in cfu per g of vegetation compared with the most active single agent), but efficacy was not increased by the addn. of vancomycin to ampicillin and imipenem. Therapy with the combination of ampicillin and imipenem may be effective for some strains of multidrug-resistant enterococcal infections.
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160
Drew, R. H. and Gallis, H. A. (1992) Azithromycin--Spectrum of Activity, Pharmacokinetics, and Clinical Applications. Pharmacotherapy 12, 161– 173, DOI: 10.1002/j.1875-9114.1992.tb04504.x
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160
Azithromycin--spectrum of activity, pharmacokinetics, and clinical applications
Drew R H; Gallis H A
Pharmacotherapy (1992), 12 (3), 161-73 ISSN:0277-0008.
Azithromycin is an azalide antimicrobial agent. Structurally related to the macrolide antibiotic erythromycin, its mechanism of activity (similar to erythromycin) is interference with bacterial protein synthesis by binding to the 50S component of the 70S ribosomal subunit. Although slightly less potent than erythromycin against gram-positive organisms, azithromycin demonstrates superior activity in vitro against a wide variety of gram-negative bacilli, including Haemophilus influenzae. Absorption is approximately 37% after a 500-mg oral dose. The large volume of distribution (23 L/kg) and low peak serum level (0.4 micrograms/ml) are consistent with data demonstrating extensive tissue distribution and intracellular accumulation. Metabolism is predominantly hepatic (to inactive metabolites), with biliary excretion a major pathway of elimination. Drug elimination is biphasic, with a terminal half-life of up to 5 days. Published trials have examined the efficacy and safety of azithromycin in the treatment of adults with upper and lower respiratory tract infections, skin and skin structure infections, streptococcal pharyngitis, and sexually transmitted diseases. Many used a 5-day course of 250 mg once daily, supplemented with a 250-mg dose on the first day of therapy. Selected trials in sexually transmitted diseases examined single 1-g doses. Promising results also were obtained with oral daily doses of 500 mg in patients with human immunoviral infection who also had Mycobacterium avium complex infection and in animals with toxoplasmosis. Adverse reactions are primarily gastrointestinal (nausea, diarrhea, abdominal pain), with minimal laboratory abnormalities reported. Gastrointestinal tolerance is better than that of erythromycin. Drug interactions have not been observed to date, although coadministration of azithromycin with a large meal may reduce absorption by up to 50%.
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Ono, S., Muratani, T., and Matsumoto, T. (2005) Mechanisms of Resistance to Imipenem and Ampicillin in Enterococcus Faecalis. Antimicrob. Agents Chemother. 49, 2954– 2958, DOI: 10.1128/AAC.49.7.2954-2958.2005
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Mechanisms of resistance to imipenem and ampicillin in Enterococcus faecalis
Ono, Seiji; Muratani, Tetsuro; Matsumoto, Tetsuro
Antimicrobial Agents and Chemotherapy (2005), 49 (7), 2954-2958CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
We found ampicillin- and imipenem-resistant isolates of vanA-possessing Enterococcus faecalis with MICs of 8 to 16 μg/mL and 4 to 32 μg/mL, resp. There have been few reports about penicillin- and imipenem-resistant E. faecalis. Two mechanisms of beta-lactam resistance in E. faecalis, the prodn. of beta-lactamase and the overprodn. of penicillin-binding proteins (PBPs), have been reported. The resistant isolates in the current study did not produce any beta-lactamases and anal. of the PBPs showed no overprodn. However, the affinities of PBP4 for beta-lactams in the resistant strains were lower than those of susceptible strains but the affinities of other PBPs for beta-lactams did not change. Accordingly, whole pbp4 fragments from these resistant isolates were sequenced. Two amino acid substitutions at positions 520 and 605 were obsd. in the highly resistant strains compared to the susceptible ones, Pro520Ser and Tyr605His, and a single Tyr605His amino acid substitution was found in the low-resistance strains. These two point mutations exist in the region between the active-site-defining motifs SDN and KTG of the penicillin-binding domain, the main target of beta-lactams. A strong correlation was seen between these substitutions and decreasing affinities of PBP4 to beta-lactams. In E. faecalis, resistance due to mutations in PBPs has not been reported, though it has in Enterococcus faecium. Our results suggest that development of high-level resistance to penicillins and imipenem depends on point mutations of PBP4 at positions 520 and 605.
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162
Brumfitt, W. and Hamilton-Miller, J. M. (1993) Reassessment of the Rationale for the Combinations of Sulphonamides with Diaminopyrimidines. J. Chemother. 5, 465– 469, DOI: 10.1080/1120009X.1993.11741097
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Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines
Brumfitt W; Hamilton-Miller J M
Journal of chemotherapy (Florence, Italy) (1993), 5 (6), 465-9 ISSN:1120-009X.
Trimethoprim is the best known inhibitor of bacterial dihydrofolate reductase. Initially, this was always combined with sulphamethoxazole. It was later combined with other sulphonamides (eg. sulphamoxole, sulphadiazine or sulfametopyrazine), but the sulphonamide moiety as a contributor to clinical efficacy was increasingly questioned. Thus, in 1979 (in UK) trimethoprim alone was introduced. Justification for the combination was based on: (a) synergy occurs in vitro (b) bactericidal activity, while the two components are bacteriostatic (c) the emergence of resistance was claimed to be lower. However, these claims were not substantiated by studying the microbiological and pharmacokinetic properties of trimethoprim and the sulphonamides, but most importantly by the results of clinical trials. These show that in most indications, trimethoprim alone is as good, cheaper and causes considerably fewer adverse events than use with a sulphonamide. For urinary infections most agree that monotherapy is best. In respiratory infections diaminopyrimidines have relatively poor activity against important pathogens, eg pneumococci and especially Moraxella catarrhalis. It could be argued in these case that the addition of a sulphonamide may increase therapeutic efficacy. This can only be resolved by large clinical trials. In brucellosis and gonorrhoea, where sulphonamides are more microbiologically active than diaminopyrimidines, it is likely that combination with another antibiotic is needed. However, too much reliance must not be placed on extrapolating from trimethoprim to other diaminopyrimidines; conclusions should be drawn from work using the other compounds.
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Voeller, D., Kovacs, J., Andrawis, V., Chu, E., Masur, H., and Allegra, C. (1994) Interaction of Pneumocystis Carinii Dihydropteroate Synthase with Sulfonamides and Diaminodiphenyl Sulfone (Dapsone). J. Infect. Dis. 169, 456– 459, DOI: 10.1093/infdis/169.2.456
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interaction of Pneumocystis carinii dihydropteroate synthase with sulfonamides and diaminodiphenyl sulfone (Dapsone)
Voeller, Donna; Kovacs, Joseph; Andrawis, Vivian; Chu, Edward; Masur, Henry; Allegra, Carmen
Journal of Infectious Diseases (1994), 169 (2), 456-9CODEN: JIDIAQ; ISSN:0022-1899.
Dihydropteroate synthase is the target enzyme for the sulfonamide compds., which are the mainstay of therapy for Pneumocystis carinii pneumonia, a common infection in patients with impaired immunity. The stability of this enzyme, its kinetic consts. with respect to substrates, and the 50% inhibitory concn. (IC50) of several sulfonamides and the sulfone dapsone have been characterized using both cell-free and intact organism assay systems. Stability of the enzyme is dependent on storage temp., reducing reagents, and to a lesser extent, protease inhibitors. The sulfonamides sulfadiazine and sulfamethoxazole were highly potent inhibitors of P. carinii dihydropteroate synthase with IC50s of 0.42 and 0.71 μM, resp. Dapsone had equiv. potency when compared with the most potent sulfonamides tested in both assay systems. Data suggest that sulfamethoxazole, sulfadiazine, and dapsone may represent equiv. choices as P. carinii dihydropteroate synthase inhibitors, assuming an equiv. in vivo drug exposure can be achieved.
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Greenwood, D. and O’Grady, F. (1976) Activity and Interaction of Trimethoprim and Sulphamethoxazole against Escherichia Coli. J. Clin. Pathol. 29, 162– 166, DOI: 10.1136/jcp.29.2.162
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Activity and interaction of trimethoprim and sulfamethoxazole against Escherichia coli
Greenwood, D.; O'Grady, F.
Journal of Clinical Pathology (1976), 29 (2), 162-6CODEN: JCPAAK; ISSN:0021-9746.
Studies of the activity of trimethoprim lactate (I lactate) [23256-42-0] and sulfamethoxazole (II) [723-46-6] alone and in combination [8064-90-2] against a sensitive strain of Escherichia coli showed that in a static system in which the conditions of exposure of bacteria to drug resembled those of conventional min. inhibitory concn. (MIC) titrns., both I and II exhibited antibacterial activity at concns. well below the conventionally detd. MIC, but regrowth occurred at these concns. during the overnight incubation period due to the emergence of adaptively resistant bacteria. Tests of combined drug action in the static turbidimetric system revealed even more synergic interaction than was apparent in conventional MIC tests, suggesting that an important component of overall synergic interaction is the mutual suppression of adaptive resistance to the other agent. Studies in an in vitro model which simulates the hydrokinetic features of the urinary bladder showed that concns. of I and II below the conventionally detd. MIC inhibited the growth even of extremely dense bacterial populations so long as the concn. of drug was maintained. The response of cultures exposed to combinations of I and II in this system was so dominated by the effect of I that no synergic interaction with II was noted at concns. of the drugs which are achievable in urine.
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Matsuura, M., Nakazawa, H., Hashimoto, T., and Mitsuhashi, S. (1980) Combined Antibacterial Activity of Amoxicillin with Clavulanic Acid against Ampicillin-Resistant Strains. Antimicrob. Agents Chemother. 17, 908– 911, DOI: 10.1128/AAC.17.6.908
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165
Combined antibacterial activity of amoxicillin with clavulanic acid against ampicillin-resistant strains
Matsuura, M.; Nakazawa, H.; Hashimoto, T.; Mitsuhashi, S.
Antimicrobial Agents and Chemotherapy (1980), 17 (6), 908-11CODEN: AMACCQ; ISSN:0066-4804.
Strains of bacteria resistant to beta-lactam antibiotics have been increasing in no. and are becoming troublesome in clin. medicine. The in vitro antibacterial activity of amoxicillin (I) [26787-78-0] combined with clavulanic acid [58001-44-8] was detd. on selected ampicillin [69-53-4]-resistant clin. isolates. Synergistic effects were produced by I with clavulanic acid against ampicillin-resistant strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and Bacteroides fragilis. Inhibition of the beta-lactamases produced by the ampicillin-resistant strains was confirmed, esp. against the penicillinases mediated by the R factor and the cephalosporinases produced by P. vulgaris and B. fragilis. The inhibitory effect of clavulanic acid against beta-lactamases was irreversible because of the high affinity of clavulanic acid for the enzymes.
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166
Brogden, R. N., Carmine, A., Heel, R. C., Morley, P. A., Speight, T. M., and Avery, G. S. (1981) Amoxycillin/Clavulanic Acid: A Review of Its Antibacterial Activity, Pharmacokinetics and Therapeutic Use. Drugs 22, 337– 362, DOI: 10.2165/00003495-198122050-00001
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166
Amoxycillin/clavulanic acid: a review of its antibacterial activity, pharmacokinetics and therapeutic use
Brogden, R. N.; Carmine, A.; Heel, R. C.; Morley, P. A.; Speight, T. M.; Avery, G. S.
Drugs (1981), 22 (5), 337-62CODEN: DRUGAY; ISSN:0012-6667.
A review with many refs. on the pharmacol. of the amoxycillin-clavulanic acid mixt. [79198-29-1].
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Breidenstein, E. B. M., Courvalin, P., and Meziane-Cherif, D. (2015) Antimicrobial Activity of Plectasin NZ2114 in Combination with Cell Wall Targeting Antibiotics Against VanA-Type Enterococcus Faecalis. Microb. Drug Resist. 21, 373– 379, DOI: 10.1089/mdr.2014.0221
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167
Antimicrobial Activity of Plectasin NZ2114 in Combination with Cell Wall Targeting Antibiotics Against VanA-Type Enterococcus faecalis
Breidenstein, Elena B. M.; Courvalin, Patrice; Meziane-Cherif, Djalal
Microbial Drug Resistance (New Rochelle, NY, United States) (2015), 21 (4), 373-379CODEN: MDREFJ; ISSN:1076-6294. (Mary Ann Liebert, Inc.)
Antimicrobial peptide plectasin targeting bacterial cell wall precursor Lipid II has been reported to be active against benzylpenicillin-resistant Streptococcus pneumoniae but less potent against vancomycin-resistant enterococci than their susceptible counterparts. The aim of this work was to test plectasin NZ2114 in combination with cell wall targeting antibiotics on vancomycin-resistant Enterococcus faecalis. The activity of antibiotic combinations was evaluated against VanA-type vancomycin-resistant E. faecalis strain BM4110/pIP816-1 by disk agar-induction, double-disk assay, detn. of fractional inhibitory concn. (FIC) index, and time-kill curve. The results indicated that plectasin NZ2114 was synergistic in combination with teicoplanin, moenomycin, and dalbavancin but not with vancomycin, telavancin, penicillin G, bacitracin, ramoplanin, daptomycin, and fosfomycin. To gain an insight into the synergism, we tested other cell wall antibiotic combinations. Interestingly, synergy was obsd. between teicoplanin or moenomycin and the majority of the antibiotics tested; however, vancomycin was only synergistic with penicillin G. Other cell wall active antibiotics such as ramoplanin, bacitracin, and fosfomycin did not synergize. It appeared that most of the synergies obsd. involved inhibition of the transglycosylation step in peptidoglycan synthesis. These results suggest that teicoplanin, dalbavancin, vancomycin, and telavancin, although they all bind to the C-terminal D-Ala-D-Ala of Lipid II, might act on different stages of cell wall synthesis.
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Schneider, T. and Sahl, H. G. (2010) An Oldie but a Goodie - Cell Wall Biosynthesis as Antibiotic Target Pathway. Int. J. Med. Microbiol. 300, 161– 169, DOI: 10.1016/j.ijmm.2009.10.005
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168
An oldie but a goodie - cell wall biosynthesis as antibiotic target pathway
Schneider, Tanja; Sahl, Hans-Georg
International Journal of Medical Microbiology (2010), 300 (2-3), 161-169CODEN: IMEMFV; ISSN:1438-4221. (Elsevier GmbH)
A review. Bacterial cell wall biosynthesis represents the target pathway for penicillin, the first antibiotic that was clin. applied on a large scale. Penicillin, by means of its beta-lactam ring, inhibits a no. of enzymes which participate in inserting monomeric cell wall building blocks into the cell wall polymer and which have been termed penicillin-binding proteins (PBPs). Ever since the introduction of penicillin, hundreds of beta-lactam antibiotics have been developed and details of their mol. activities elaborated. Meanwhile, various addnl. classes of antibiotics have been described, which inhibit the same pathway, yet use target mols. others than the PBPs. Such classes include the glycopeptide antibiotics, lipopeptide and lipodepsipeptide antibiotics, the lantibiotics and various other natural product antibiotics with comparatively complex structures. They usually target the membrane-bound steps of the biosynthesis pathway and the highly conserved lipid-bound intermediates of the building block such as lipid II, which represents a particular "Achilles' heel" for antibiotic attack. With in-depth anal. of the activity of more recently identified inhibitors and with the availability of novel techniques for studying prokaryotic cell biol., new insights were obtained into the mol. organization of the cell wall biosynthesis machinery and its interconnections with other vital cellular processes such as cell division. This, in turn, provides hints for new targets to be exploited and for the development of novel cell wall biosynthesis inhibitors.
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Steinmann, J., Buer, J., Pietschmann, T., and Steinmann, E. (2013) Anti-Infective Properties of Epigallocatechin-3-Gallate (EGCG), a Component of Green Tea. Br. J. Pharmacol. 168, 1059– 1073, DOI: 10.1111/bph.12009
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Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea
Steinmann, J.; Buer, J.; Pietschmann, T.; Steinmann, E.
British Journal of Pharmacology (2013), 168 (5), 1059-1073CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
A review. The consumption of green tea (Camellia sinensis) has been shown to have many physiol. and pharmacol. health benefits. In the past two decades several studies have reported that epigallocatechin-3-gallate (EGCG), the main constituent of green tea, has anti-infective properties. Antiviral activities of EGCG with different modes of action have been demonstrated on diverse families of viruses, such as Retroviridae, Orthomyxoviridae and Flaviviridae and include important human pathogens like human immunodeficiency virus, influenza A virus and the hepatitis C virus. Furthermore, the mol. interferes with the replication cycle of DNA viruses like hepatitis B virus, herpes simplex virus and adenovirus. Most of these studies demonstrated antiviral properties within physiol. concns. of EGCG in vitro. In contrast, the min. inhibitory concns. against bacteria were 10-100-fold higher. Nevertheless, the antibacterial effects of EGCG alone and in combination with different antibiotics have been intensively analyzed against a no. of bacteria including multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Furthermore, the catechin EGCG has antifungal activity against human-pathogenic yeasts like Candida albicans. Although the mechanistic effects of EGCG are not fully understood, there are results indicating that EGCG binds to lipid membranes and affects the folic acid metab. of bacteria and fungi by inhibiting the cytoplasmic enzyme dihydrofolate reductase. This review summarizes the current knowledge and future perspectives on the antibacterial, antifungal and antiviral effects of the green tea constituent EGCG.
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Zhao, W.-H., Hu, Z.-Q., Hara, Y., and Shimamura, T. (2002) Inhibition of Penicillinase by Epigallocatechin Gallate Resulting in Restoration of Antibacterial Activity of Penicillin against Penicillinase-Producing Staphylococcus Aureus. Antimicrob. Agents Chemother. 46, 2266– 2268, DOI: 10.1128/AAC.46.7.2266-2268.2002
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Inhibition of penicillinase by epigallocatechin gallate resulting in restoration of antibacterial activity of penicillin against penicillinase-producing Staphylococcus aureus
Zhao, Wei-Hua; Hu, Zhi-Qing; Hara, Yukihiko; Shimamura, Tadakatsu
Antimicrobial Agents and Chemotherapy (2002), 46 (7), 2266-2268CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
The combination of epigallocatechin gallate (EGCg, a main constituent of tea catechins) with penicillin showed synergism against 21 clin. isolates of penicillinase-producing Staphylococcus aureus. Besides binding directly to peptidoglycan, the inhibition of penicillinase activity by EGCg is responsible for the synergism. EGCg inhibited the penicillinase activity in a dose-dependent fashion, with a 50% inhibitory concn. of 10 μg/mL.
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Berti, A. D., Theisen, E., Sauer, J.-D., Nonejuie, P., Olson, J., Pogliano, J., Sakoulas, G., Nizet, V., Proctor, R. A., and Rose, W. E. (2016) Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus Aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for Beta-Lactam-Daptomycin Synergy. Antimicrob. Agents Chemother. 60, 451– 458, DOI: 10.1128/AAC.02071-15
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Penicillin binding protein 1 is important in the compensatory response of Staphylococcus aureus to daptomycin-induced membrane damage and is a potential target for β-Lactam-daptomycin synergy
Berti, Andrew D.; Theisen, Erin; Sauer, John-Demian; Nonejuie, Poochit; Olson, Joshua; Pogliano, Joseph; Sakoulas, George; Nizet, Victor; Proctor, Richard A.; Rose, Warren E.
Antimicrobial Agents and Chemotherapy (2016), 60 (1), 451-458CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of β-lactam antibiotics. This effect is more pronounced with β-lactam antibiotics that exhibit avid binding to penicillin-binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the pbpA transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of pbpB, pbpC, and pbpD, encoding PBP2, PBP3, and PBP4, resp., remained unchanged. Using a MRSA COL strain with pbpA under an inducible promoter, increased pbpA transcription was accompanied by reduced susceptibility to, and killing by, DAP in vitro. Exposure to β-lactams that preferentially inactivate PBP1 was not assocd. with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-mol. basis. Combination exposure in an in vitro pharmacokinetic/pharmacodynamic model system with β-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAP-nafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO), or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective). Compared to β-lactams with poor PBP1 binding specificity, exposure of S. aureus to DAP plus PBP1-selective β-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP-β-lactam combination therapy for serious MRSA infections, particularly when the β-lactam undermines the PBP1-mediated compensatory response.
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Smith, J. R., Barber, K. E., Raut, A., Aboutaleb, M., Sakoulas, G., and Rybak, M. J. (2015) Beta-Lactam Combinations with Daptomycin Provide Synergy against Vancomycin-Resistant Enterococcus Faecalis and Enterococcus Faecium. J. Antimicrob. Chemother. 70, 1738– 1743, DOI: 10.1093/jac/dkv007
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β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium
Smith, Jordan R.; Barber, Katie E.; Raut, Animesh; Aboutaleb, Mostafa; Sakoulas, George; Rybak, Michael J.
Journal of Antimicrobial Chemotherapy (2015), 70 (6), 1738-1743CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. The objective here was to conduct combination MIC and time-kill expts. to evaluate BL synergy with daptomycin against enterococci. Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill expts. Daptomycin at 0.5 × MIC was used in combination with BL at biol. free concn. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labeled daptomycin (BoDipy) expts. Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill expts., ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial redn. at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin expts., ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001). Conclusions: The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clin. research involving daptomycin combinations is warranted.
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Koppen, B. C., Mulder, P. P. G., de Boer, L., Riool, M., Drijfhout, J. W., and Zaat, S. A. J. (2019) Synergistic Microbicidal Effect of Cationic Antimicrobial Peptides and Teicoplanin against Planktonic and Biofilm-Encased Staphylococcus Aureus. Int. J. Antimicrob. Agents 53, 143– 151, DOI: 10.1016/j.ijantimicag.2018.10.002
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Synergistic microbicidal effect of cationic antimicrobial peptides and teicoplanin against planktonic and biofilm-encased Staphylococcus aureus
Koppen, Bruce C.; Mulder, Patrick P. G.; de Boer, Leonie; Riool, Martijn; Drijfhout, Jan W.; Zaat, Sebastian A. J.
International Journal of Antimicrobial Agents (2019), 53 (2), 143-151CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
Antibiotic resistance and biofilm formation are the main reasons for failure in treatment of bacterial infections. This study aimed to identify synergistic combinations of conventional antibiotics and novel synthetic antimicrobial and antibiofilm peptides (SAAPs) inspired by the structures of the natural human cationic peptides LL-37 and thrombocidin-1 (TC-1). The LL-37-inspired lead peptide SAAP-148 was combined with antibiotics of different classes against Staphylococcus aureus, and showed synergy with teicoplanin. Synergy with teicoplanin was also obsd. with LL-37, the LL-37-inspired SAAP-276 and the TC-1-inspired TC84. Interestingly, no synergy was obsd. against Staphylococcus epidermidis. Furthermore, teicoplanin combined with SAAP-148 or SAAP-276 showed strong interaction against S. aureus biofilms. The dltABCD operon and the mprF gene in S. aureus conferred resistance to LL-37, but SAAP-148 proved to be indifferently potent against wild-type, ΔdltA and ΔmprF S. aureus strains. When used alone, relatively high concns. of both LL-37 and teicoplanin (30-120 μM and 4-32 mg/L, resp.) were required to kill S. aureus. Resistance to LL-37 in S. aureus was overcome by combined use of teicoplanin and LL-37. Thus, teicoplanin potentiates peptide LL-37, enhancing the efficacy of the innate defense, and combining the novel peptides with teicoplanin offers potential for enhanced efficacy of treatment of S. aureus infections, including biofilms.
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Fernandez-Cuenca, F., Martinez-Martinez, L., Pascual, A., and Perea, E. J. (2003) In Vitro Activity of Azithromycin in Combination with Amikacin, Ceftazidime, Ciprofloxacin or Imipenem against Clinical Isolates of Acinobacter Baumannii. Chemotherapy 49, 24– 26, DOI: 10.1159/000069774
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In vitro activity of azithromycin in combination with amikacin, ceftazidime, ciprofloxacin or imipenem against clinical isolates of Acinetobacter baumannii
Fernandez-Cuenca, Felipe; Martinez-Martinez, Luis; Pascual, Alvaro; Perea, Evelio J.
Chemotherapy (Basel, Switzerland) (2003), 49 (1-2), 24-26CODEN: CHTHBK; ISSN:0009-3157. (S. Karger AG)
The in vitro activity of the two-drug combinations of azithromycin with amikacin, ceftazidime, ciprofloxacin or imipenem against five clonally unrelated strains of Acinetobacter baumannii were evaluated. Synergy studies were performed by the checkerboard microtiter method. The fractional inhibitory concn. (FIC) index was calcd. for each drug combination. None of the 4 combinations tested was antagonistic. The combination of azithromycin and ceftazidime was synergistic (FIC index ≤0.5) for one strain and partially synergistic (FIC index 0.75) for another strain. An additive effect (FIC index = 1) was obsd. for the combinations of azithromycin with imipenem (two strains) or ceftazidime (one strain). The activities of the other combinations were indifferent (FIC index range from 1.5 to 2.5). It is concluded that azithromycin combined with ceftazidime has moderate synergistic activity against some multiresistant A. baumannii.
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Sertcelik, A., Baran, I., Akinci, E., Mumcuoglu, I., and Bodur, H. (2019) Synergistic Activities of Colistin Combinations with Meropenem, Sulbactam, Minocycline, Disodium Fosfomycin, or Vancomycin Against Different Clones of Carbapenem-Resistant Acinetobacter Baumannii Strains. Microb. Drug Resist. DOI: 10.1089/mdr.2019.0088 .
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Langeveld, W. T., Veldhuizen, E. J. A., and Burt, S. A. (2014) Synergy between Essential Oil Components and Antibiotics: A Review. Crit. Rev. Microbiol. 40, 76– 94, DOI: 10.3109/1040841X.2013.763219
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Synergy between essential oil components and antibiotics: a review
Langeveld, Wendy T.; Veldhuizen, Edwin J. A.; Burt, Sara A.
Critical Reviews in Microbiology (2014), 40 (1), 76-94CODEN: CRVMAC; ISSN:1040-841X. (Informa Healthcare)
A review. With the increase in antibiotic-resistant bacteria and the lack of new antibiotics being brought onto the market, alternative strategies need to be found to cope with infections resulting from drug-resistant bacteria. A possible soln. may be to combine existing antibiotics with phytochems. to enhance the efficacy of antibiotics. A group of phytochems. that is said to have such effects, according to in vitro studies, is essential oils (EOs) and their components. Amongst others, EOs contg. carvacrol, cinnamaldehyde, cinnamic acid, eugenol and thymol can have a synergistic effect in combination with antibiotics. Several modes of action have been put forward by which antibiotics and the essential oil components may act synergistically, such as by affecting multiple targets; by physicochem. interactions and inhibiting antibacterial-resistance mechanisms. Many reported assays show additivity or moderate synergism, indicating that EOs may offer possibilities for reducing antibiotic use.
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Owen, L. and Laird, K. (2018) Synchronous Application of Antibiotics and Essential Oils: Dual Mechanisms of Action as a Potential Solution to Antibiotic Resistance. Crit. Rev. Microbiol. 44, 414– 435, DOI: 10.1080/1040841X.2018.1423616
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Synchronous application of antibiotics and essential oils: dual mechanisms of action as a potential solution to antibiotic resistance
Owen, Lucy; Laird, Katie
Critical Reviews in Microbiology (2018), 44 (4), 414-435CODEN: CRVMAC; ISSN:1040-841X. (Taylor & Francis Ltd.)
A review. Antibiotic resistance has increased dramatically in recent years, yet the antibiotic pipeline has stalled. New therapies are therefore needed to continue treating antibiotic resistant infections. One potential strategy currently being explored is the use of non-antibiotic compds. to potentiate the activity of currently employed antibiotics. Many natural products including Essential Oils (EOs) possess broad spectrum antibacterial activity and so have been investigated for this purpose. This article aims to review recent literature concerning the antibacterial activity of EOs and their interactions with antibiotics, with consideration of dual mechanisms of action of EOs and antibiotics as a potential soln. to antibiotic resistance. Synergistic interactions between EOs and their components with antibiotics have been reported, including several instances of antibiotic resensitization in resistant isolates, in support of this strategy to control antibiotic resistance. However, a lack of consistency in methods and interpretation criteria makes drawing conclusions of efficacy of studied combinations difficult. Synergistic effects are often not explored beyond preliminary identification of antibacterial interactions and mechanism of action is rarely defined, despite many hypotheses and recommendations for future study. Much work is needed to fully understand EO-antibiotic assocns. before they can be further developed into novel antibacterial formulations.
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Mathur, H., Field, D., Rea, M. C., Cotter, P. D., Hill, C., and Ross, R. P. (2017) Bacteriocin-Antimicrobial Synergy: A Medical and Food Perspective. Front. Microbiol. 8, 1205, DOI: 10.3389/fmicb.2017.01205
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Bacteriocin-Antimicrobial Synergy: A Medical and Food Perspective
Mathur Harsh; Rea Mary C; Cotter Paul D; Mathur Harsh; Field Des; Rea Mary C; Cotter Paul D; Hill Colin; Ross R Paul; Field Des; Hill Colin; Ross R Paul
Frontiers in microbiology (2017), 8 (), 1205 ISSN:1664-302X.
The continuing emergence of multi-drug resistant pathogens has sparked an interest in seeking alternative therapeutic options. Antimicrobial combinatorial therapy is one such avenue. A number of studies have been conducted, involving combinations of bacteriocins with other antimicrobials, to circumvent the development of antimicrobial resistance and/or increase antimicrobial potency. Such bacteriocin-antimicrobial combinations could have tremendous value, in terms of reducing the likelihood of resistance development due to the involvement of two distinct mechanisms of antimicrobial action. Furthermore, antimicrobial synergistic interactions may also have potential financial implications in terms of decreasing the costs of treatment by reducing the concentration of an expensive antimicrobial and utilizing it in combination with an inexpensive one. In addition, combinatorial therapies with bacteriocins can broaden antimicrobial spectra and/or result in a reduction in the concentration of an antibiotic required for effective treatments to the extent that potentially toxic or adverse side effects can be reduced or eliminated. Here, we review studies in which bacteriocins were found to be effective in combination with other antimicrobials, with a view to targeting clinical and/or food-borne pathogens. Furthermore, we discuss some of the bottlenecks which are currently hindering the development of bacteriocins as viable therapeutic options, as well as addressing the need to exercise caution when attempting to predict clinical outcomes of bacteriocin-antimicrobial combinations.
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Wolska, K. I., Grzes, K., and Kurek, A. (2012) Synergy between Novel Antimicrobials and Conventional Antibiotics or Bacteriocins. Pol. J. Microbiol. 61, 95– 104, DOI: 10.33073/pjm-2012-012
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Synergy between novel antimicrobials and conventional antibiotics or bacteriocins
Wolska, Krystyna I.; Grzes, Katarzyna; Kurek, Anna
Polish Journal of Microbiology (2012), 61 (2), 95-104CODEN: PJMOAQ; ISSN:1733-1331. (Polskie Towarzystwo Mikrobiologow)
A review. Due to the alarming spread of resistance to classic antimicrobial agents, innovative therapeutic methods to combat antibiotic-resistant bacterial pathogens are urgently required. This minireview examines the enhancement of antibiotic efficacy by their combination with new antimicrobials, such as plant-derived compds., metal ions and nanoparticles and bacteriophage lytic enzymes. The mechanisms of the obsd. synergy are also described. The promising results of basic research indicate that in future, combined therapy may be applied in human and veterinary medicine, agriculture and the food industry to combat bacterial pathogens.
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Wittekind, M. and Schuch, R. (2016) Cell Wall Hydrolases and Antibiotics: Exploiting Synergy to Create Efficacious New Antimicrobial Treatments. Curr. Opin. Microbiol. 33, 18– 24, DOI: 10.1016/j.mib.2016.05.006
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Cell wall hydrolases and antibiotics: exploiting synergy to create efficacious new antimicrobial treatments
Wittekind, Michael; Schuch, Raymond
Current Opinion in Microbiology (2016), 33 (), 18-24CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)
A review. Cell wall hydrolases (CWH) are enzymes that build, remodel and degrade peptidoglycan within bacterial cell walls and serve essential roles in cell-wall metab., bacteriophage adsorption and bacteriolysis, environmental niche expansion, as well as eukaryotic innate immune defense against bacterial infection. Some CWHs, when tested as recombinant purified proteins, have been shown to have bactericidal activities both as single agents and in combinations with other antimicrobials, displaying synergies in vitro and potent activities in animal models of infection greater than the single agents alone. We summarize in vitro, in vivo, and mechanistic studies that illustrate ACWH synergy with antibiotics, antimicrobial peptides, and other ACWHs, underscoring the overall synergistic potential of the ACWH class.
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Zusman, O., Avni, T., Leibovici, L., Adler, A., Friberg, L., Stergiopoulou, T., Carmeli, Y., and Paul, M. (2013) Systematic Review and Meta-Analysis of in Vitro Synergy of Polymyxins and Carbapenems. Antimicrob. Agents Chemother. 57, 5104– 5111, DOI: 10.1128/AAC.01230-13
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Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems
Zusman, Oren; Avni, Tomer; Leibovici, Leonard; Adler, Amos; Friberg, Lena; Stergiopoulou, Theodouli; Carmeli, Yehuda; Paul, Mical
Antimicrobial Agents and Chemotherapy (2013), 57 (10), 5104-5111CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Our objective was to examine the evidence of in vitro synergy of polymyxin-carbapenem combination therapy against Gram-neg. bacteria (GNB). A systematic review and meta-anal. were performed. All studies examg. in vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concn. index of ≤0.5 or a >2-log redn. in CFU, were pooled sep. for time-kill, checkerboard, and Etest methods in a mixed-effect meta-anal. of rates. We examd. whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for Acinetobacter baumannii, 44% (95% CI, 30 to 59%) for Klebsiella pneumoniae, and 50% (95% CI, 30 to 69%) for Psudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance development in vitro. The combination of a carbapenem with a polymyxin against GNB, esp. A. baumannii, is supported in vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examd. in clin. studies.
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Lenhard, J. R., Nation, R. L., and Tsuji, B. T. (2016) Synergistic Combinations of Polymyxins. Int. J. Antimicrob. Agents 48, 607– 613, DOI: 10.1016/j.ijantimicag.2016.09.014
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Synergistic combinations of polymyxins
Lenhard, Justin R.; Nation, Roger L.; Tsuji, Brian T.
International Journal of Antimicrobial Agents (2016), 48 (6), 607-613CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
A review. The proliferation of extensively drug-resistant Gram-neg. pathogens has necessitated the therapeutic use of colistin and polymyxin B. However, treatment failures with polymyxin monotherapies and the emergence of polymyxin resistance have catalyzed the search for polymyxin combinations that synergistically kill polymyxin-susceptible and -resistant organisms. This mini-review examines recent (2011-2016) in vitro and in vivo studies that have attempted to identify synergistic polymyxin combinations against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Clin. evidence for the use of combination regimens is also discussed.
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Alakomi, H.-L., Saarela, M., and Helander, I. M. (2003) Effect of EDTA on Salmonella Enterica Serovar Typhimurium Involves a Component Not Assignable to Lipopolysaccharide Release. Microbiology 149, 2015– 2021, DOI: 10.1099/mic.0.26312-0
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Effect of EDTA on Salmonella enterica serovar Typhimurium involves a component not assignable to lipopolysaccharide release
Alakomi, H.-L.; Saarela, M.; Helander, I. M.
Microbiology (Reading, United Kingdom) (2003), 149 (8), 2015-2021CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
The effect of EDTA on Salmonella enterica serovar Typhimurium was studied in different growth phases with cells grown with or without Ca2+ and Mg2+ supplementation. EDTA affected the outer membrane much more strongly in the early exponential phase than in the mid- or late exponential phase, as indicated by uptake of 1-N-phenylnaphthylamine (a nonpolar hydrophobic probe, Mr 219) and detergent (SDS) susceptibility. This effect was, however, not paralleled by LPS release (detd. by measuring LPS-specific fatty acids or 14C-labeled LPS in cell-free supernatants, per a standardized cell d.), which remained unchanged as a function of the growth curve. The conclusion from these results is that in the early exponential phase the effect of EDTA in S. enterica involves a component that is independent of LPS release.
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Vaara, M. (1992) Agents That Increase the Permeability of the Outer Membrane. Microbiol. Rev. 56, 395– 411, DOI: 10.1128/MMBR.56.3.395-411.1992
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184
Agents that increase the permeability of the outer membrane
Vaara, Martti
Microbiological Reviews (1992), 56 (3), 395-411CODEN: MBRED3; ISSN:0146-0749.
A review with 241 refs. on cationic agents and chelators as outer membrane permeabilizers, the mol. mechanism of outer membrane permeability increase, and bacterial strains resistant to the permeabilizers.
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Bellio, P., Luzi, C., Mancini, A., Cracchiolo, S., Passacantando, M., Di Pietro, L., Perilli, M., Amicosante, G., Santucci, S., and Celenza, G. (2018) Cerium Oxide Nanoparticles as Potential Antibiotic Adjuvant. Effects of CeO2 Nanoparticles on Bacterial Outer Membrane Permeability. Biochim. Biophys. Acta, Biomembr. 1860, 2428– 2435, DOI: 10.1016/j.bbamem.2018.07.002
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Cerium oxide nanoparticles as potential antibiotic adjuvant. Effects of CeO2 nanoparticles on bacterial outer membrane permeability
Bellio, Pierangelo; Luzi, Carla; Mancini, Alisia; Cracchiolo, Salvatore; Passacantando, Maurizio; Di Pietro, Letizia; Perilli, Mariagrazia; Amicosante, Gianfranco; Santucci, Sandro; Celenza, Giuseppe
Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (11), 2428-2435CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Therapeutic options against Multi Drug Resistant (MDR) pathogens are limited and the overall strategy would be the development of adjuvants able to enhance the activity of therapeutically available antibiotics. Non-specific outer membrane permeabilizer, like metal-oxide nanoparticles, can be used to increase the activity of antibiotics in drug-resistant pathogens. The study aims to investigate the effect of cerium oxide nanoparticles (CeO2 NPs) on bacterial outer membrane permeability and their application in increasing the antibacterial activity of antibiotics against MDR pathogens. The ability of CeO2 NPs to permeabilize Gram-neg. bacterial outer membrane was investigated by calcein-loaded liposomes. The extent of the damage was evaluated using lipid vesicles loaded with FITC-dextran probes. The effect on bacterial outer membrane was evaluated by measuring the coeff. of permeability at increasing concns. of CeO2 NPs. The interaction between CeO2 NPs and beta-lactams was evaluated by chequerboard assay against a Klebsiella pneumoniae clin. isolate expressing high levels of resistance against those antibiotics. Calcein leakage increases as NPs concns. increase while no leakage was obsd. in FITC-dextran loaded liposomes. In Escherichia coli the outer membrane permeability coeff. increases in presence of CeO2 NPs. The antibacterial activity of beta-lactam antibiotics against K. pneumoniae was enhanced when combined with NPs. CeO2 NPs increases the effectiveness of antimicrobials which activity is compromised by drug resistance mechanisms. The synergistic effect is the result of the interaction of NPs with the bacterial outer membrane. The low toxicity of CeO2 NPs makes them attractive as antibiotic adjuvants against MDR pathogens.
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Saikia, K. and Chaudhary, N. (2018) Antimicrobial Peptides from C-Terminal Amphipathic Region of E. Coli FtsA. Biochim. Biophys. Acta, Biomembr. 1860, 2506– 2514, DOI: 10.1016/j.bbamem.2018.09.011
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Antimicrobial peptides from C-terminal amphipathic region of E. coli FtsA
Saikia, Karabi; Chaudhary, Nitin
Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (12), 2506-2514CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
Antimicrobial peptides constitute an indispensable component of innate immune system in organisms ranging from bacteria to man. Despite this, peptides lag far behind the conventional antibiotics in treating infections. The menace of multidrug-resistant bacteria, however, has revived the antimicrobial peptide research. We reasoned that the membrane-binding regions of bacterial proteins could be purposed to combat them. Here, we identify potent antimicrobial peptides from the C-terminal amphipathic helix of E. coli FtsA protein. The 11 and 13-residue peptides exhibited activity against E. coli, gentamicin-resistant MRSA, and C. albicans. The activity is little affected by the presence of salt and divalent cations. The peptides preferentially bind to the neg.-charged membranes as indicated by tryptophan fluorescence studies. The peptides permeabilize the E. coli outer and inner membranes at very promising concns. suggesting membrane-disruption as one of the mechanisms of killing.
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Wiese, A., Gutsmann, T., and Seydel, U. (2003) Towards Antibacterial Strategies: Studies on the Mechanisms of Interaction between Antibacterial Peptides and Model Membranes. J. Endotoxin Res. 9, 67– 84, DOI: 10.1179/096805103125001441
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187
Towards antibacterial strategies: studies on the mechanisms of interaction between antibacterial peptides and model membranes
Wiese, Andre; Gutsmann, Thomas; Seydel, Ulrich
Journal of Endotoxin Research (2003), 9 (2), 67-84CODEN: JENREB; ISSN:0968-0519. (Maney Publishing)
A review. Lipopolysaccharides (LPSs) play a dual role as inflammation-inducing and as membrane-forming mols. The former role attracts significantly more attention from scientists, possibly because it is more closely related to sepsis and septic shock. This review aims to focus the reader's attention to the other role, the function of LPS as the major constituent of the outer layer of the outer membrane of Gram-neg. bacteria, in particular those of enterobacterial strains. In this function, LPS is a necessary component of the cell envelope and guarantees survival of the bacterial organism. At the same time, it represents the first target for attacking mols. which may either be synthesized by the host's innate or adaptive immune system or administered to the human body. The interaction of these mols. with the outer membrane may not only directly cause the death of the bacterial organism, but may also lead to the release of LPS into the circulation. Here, we review membrane model systems and their application for the study of mol. mechanisms of interaction of peptides such as those of the human complement system, the bactericidal/permeability-increasing protein (BPI), cationic antibacterial peptide 18 kDa (CAP18) as an example of cathelicidins, defensins, and polymyxin B (PMB). Emphasis is on elec. measurements with a reconstitution system of the lipid matrix of the outer membrane which was established in the authors' lab. as a planar asym. bilayer with one leaflet being composed solely of LPS and the other of the natural phospholipid mixt. The main conclusion, which can be drawn from these investigations, is that LPS and in general its neg. charges are the dominant determinants for specific peptide-membrane interactions. However, the detailed mechanisms of interaction, which finally lead to bacterial killing, may involve further steps and differ for different antibacterial peptides.
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Vaara, M. and Porro, M. (1996) Group of Peptides That Act Synergistically with Hydrophobic Antibiotics against Gram-Negative Enteric Bacteria. Antimicrob. Agents Chemother. 40, 1801– 1805, DOI: 10.1128/AAC.40.8.1801
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Group of peptides that act synergistically with hydrophobic antibiotics against gram-negative enteric bacteria
Vaara, Martti; Porro, Massimo
Antimicrobial Agents and Chemotherapy (1996), 40 (8), 1801-1805CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
A synthetic peptide, KFFKFFKFF, consisting of cationic lysine residues and hydrophobic phenylalanine residues was found to sensitize gram-neg. bacteria to hydrophobic and amphipathic antibiotics. At a concn. of 3 μg/mL, it decreased the MIC of rifampin for smooth, encapsulated Escherichia coli by a factor of 300. Other susceptible bacterial species included Enterobacter cloacae, Klebsiella pneumoniae, and Salmonella typhimurium, but Pseudomonas aeruginosa was resistant. Similar results were obtained with another synthetic peptide, IKFLKFLKFL. The fractional inhibitory concn. indexes for the synergism of these peptides with rifampin, erythromycin, fusidic acid, and novobiocin were very close to those detd. for the previously characterized potent outer-membrane-disorganizing agents polymyxin B nonapeptide and deacylpolymyxin B. KFFKFFKFF had direct activity against the gram-pos. organism Micrococcus strain ML36, was strongly hemolytic, and was as active on polymyxin-resistant E. coli mutants as on their parent. These three attributes made KFFKFFKFF different from polymyxin derivs. and similar to cationic detergents, such as cetylpyridinium chloride. However, whereas the MIC of cetylpyridinium chloride for E. coli is low (0.5 to 4 μg/mL), that of KFFKFFKFF is much higher (30 to 100 μg/mL). Other groups of synthetic peptides studied included polymyxin-like peptides with an intrachain disulfide bridge. Their synergism with antibiotics was less marked. Still other peptides, including KEKEKEKEKE and KKKKKKFLFL, lacked any synergism with the probe antibiotics.
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Ando, M., Kamei, R., Komagoe, K., Inoue, T., Yamada, K., and Katsu, T. (2012) In Situ Potentiometric Method to Evaluate Bacterial Outer Membrane-Permeabilizing Ability of Drugs: Example Using Antiprotozoal Diamidines. J. Microbiol. Methods 91, 497– 500, DOI: 10.1016/j.mimet.2012.09.033
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189
In situ potentiometric method to evaluate bacterial outer membrane-permeabilizing ability of drugs: Example using antiprotozoal diamidines
Ando, Makoto; Kamei, Rie; Komagoe, Keiko; Inoue, Tsuyoshi; Yamada, Keiichi; Katsu, Takashi
Journal of Microbiological Methods (2012), 91 (3), 497-500CODEN: JMIMDQ; ISSN:0167-7012. (Elsevier B.V.)
We introduced a new assay system, combining tyrocidine A and a K+-selective electrode, to evaluate the bacterial outer membrane-permeabilizing ability of drugs. Tyrocidine A, in the presence of an outer membrane permeabilizer, increased the permeability to K+ of the cytoplasmic membrane of Escherichia coli, because this antibiotic could markedly increase the permeability of phospholipid layers constituting the cytoplasmic membrane, while it acted weakly on the outer membrane. Hence, the novel function of agents increasing the permeability of the outer membrane could be examd. directly by monitoring the tyrocidine A-induced leakage of K+ from the bacterial cytoplasm using a K+-selective electrode. We found that antiprotozoal diamidines, such as diminazene, pentamidine, and 4',6-diamidino-2-phenylindole (DAPI), can increase the permeability of the bacterial outer membrane and appropriate lipophilicity is important for diamidines to permeabilize the outer membrane.
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Stokes, J. M., MacNair, C. R., Ilyas, B., French, S., Cote, J.-P., Bouwman, C., Farha, M. A., Sieron, A. O., Whitfield, C., Coombes, B. K., and Brown, E. D. (2017) Pentamidine Sensitizes Gram-Negative Pathogens to Antibiotics and Overcomes Acquired Colistin Resistance. Nat. Microbiol. 2, 17028, DOI: 10.1038/nmicrobiol.2017.28
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Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance
Stokes Jonathan M; MacNair Craig R; Ilyas Bushra; French Shawn; Cote Jean-Philippe; Farha Maya A; Sieron Arthur O; Coombes Brian K; Brown Eric D; Bouwman Catrien; Whitfield Chris
Nature microbiology (2017), 2 (), 17028 ISSN:.
The increasing use of polymyxins(1) in addition to the dissemination of plasmid-borne colistin resistance threatens to cause a serious breach in our last line of defence against multidrug-resistant Gram-negative pathogens, and heralds the emergence of truly pan-resistant infections. Colistin resistance often arises through covalent modification of lipid A with cationic residues such as phosphoethanolamine-as is mediated by Mcr-1 (ref. 2)-which reduce the affinity of polymyxins for lipopolysaccharide(3). Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections(4). The difficulty in eradicating Gram-negative bacteria is largely due to their highly impermeable outer membrane, which serves as a barrier to many otherwise effective antibiotics(5). Here, we describe an unconventional screening platform designed to enrich for non-lethal, outer-membrane-active compounds with potential as adjuvants for conventional antibiotics. This approach identified the antiprotozoal drug pentamidine(6) as an effective perturbant of the Gram-negative outer membrane through its interaction with lipopolysaccharide. Pentamidine displayed synergy with antibiotics typically restricted to Gram-positive bacteria, yielding effective drug combinations with activity against a wide range of Gram-negative pathogens in vitro, and against systemic Acinetobacter baumannii infections in mice. Notably, the adjuvant activity of pentamidine persisted in polymyxin-resistant bacteria in vitro and in vivo. Overall, pentamidine and its structural analogues represent unexploited molecules for the treatment of Gram-negative infections, particularly those having acquired polymyxin resistance determinants.
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Yarlagadda, V., Manjunath, G. B., Sarkar, P., Akkapeddi, P., Paramanandham, K., Shome, B. R., Ravikumar, R., and Haldar, J. (2016) Glycopeptide Antibiotic To Overcome the Intrinsic Resistance of Gram-Negative Bacteria. ACS Infect. Dis. 2, 132– 139, DOI: 10.1021/acsinfecdis.5b00114
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191
Glycopeptide antibiotics to overcome the intrinsic resistance of Gram-negative bacteria
Yarlagadda, Venkateswarlu; Manjunath, Goutham B.; Sarkar, Paramita; Akkapeddi, Padma; Paramanandham, Krishnamoorthy; Shome, Bibek R.; Ravikumar, Raju; Haldar, Jayanta
ACS Infectious Diseases (2016), 2 (2), 132-139CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
The emergence of drug resistance along with a declining pipeline of clin. useful antibiotics has made it vital to develop more effective antimicrobial therapeutics, particularly against difficult-to-treat Gram-neg. pathogens (GNPs). Many antibacterial agents, including glycopeptide antibiotics such as vancomycin, are inherently inactive toward GNPs because of their inability to cross the outer membrane of these pathogens. Here, the authors demonstrate that lipophilic cationic (permanent pos. charge) vancomycin analogs were able to permeabilize the outer membrane of GNPs and overcome the inherent resistance of GNPs toward glycopeptides. Unlike vancomycin, these analogs were shown to have a high activity against a variety of multidrug-resistant clin. isolates such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the murine model of carbapenem-resistant A. baumannii infection, the optimized compd. showed potent activity with no obsd. toxicity. The notable activity of these compds. is attributed to the incorporation of new membrane disruption mechanisms (cytoplasmic membrane depolarization along with outer and inner (cytoplasmic) membrane permeabilization) into vancomycin.
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Zhou, L., van Heel, A. J., Montalban-Lopez, M., and Kuipers, O. P. (2016) Potentiating the Activity of Nisin against Escherichia Coli. Front. Cell Dev. Biol. 4, 7, DOI: 10.3389/fcell.2016.00007
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192
Potentiating the Activity of Nisin against Escherichia coli
Zhou Liang; van Heel Auke J; Montalban-Lopez Manuel; Kuipers Oscar P
Frontiers in cell and developmental biology (2016), 4 (), 7 ISSN:2296-634X.
Lantibiotics are antimicrobial (methyl)lanthionine-containing peptides produced by various Gram-positive bacteria. The model lantibiotic, nisin, binds lipid II in the cell membrane. Additionally, after binding it can insert into the membrane creating a pore. Nisin can efficiently inhibit the growth of Gram-positive bacteria and resistance is rarely observed. However, the activity of lantibiotics is at least 100-fold lower against certain Gram-negative bacteria. This is caused by the fact that Gram-negative bacteria have an outer membrane that hinders the peptides to reach lipid II, which is located in the inner membrane. Improving the activity of lantibiotics against Gram-negative bacteria could be achieved if the outer membrane traversing efficiency is increased. Here, several anti-Gram-negative peptides (e.g., apidaecin 1b, oncocin), or parts thereof, were fused to the C-terminus of either a truncated version of nisin containing the first three/five rings or full length nisin. The activities of these fusion peptides were tested against Gram-negative pathogens. Our results showed that when an eight amino acids (PRPPHPRL) tail from apidaecin 1b was attached to nisin, the activity of nisin against Escherichia coli CECT101 was increased more than two times. This research presents a new and promising method to increase the anti-Gram-negative activity of lantibiotics.
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Li, Q., Montalban-Lopez, M., and Kuipers, O. P. (2018) Increasing the Antimicrobial Activity of Nisin-Based Lantibiotics against Gram-Negative Pathogens. Appl. Environ. Microbiol. 84, e00052-18 DOI: 10.1128/AEM.00052-18
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194
Schweizer, F. (2019) Enhancing Uptake of Antibiotics into Gram-Negative Bacteria Using Nonribosome-Targeting Aminoglycoside-Based Adjuvants. Future Med. Chem. 11, 1519– 1522, DOI: 10.4155/fmc-2019-0131
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Enhancing uptake of antibiotics into Gram-negative bacteria using nonribosome-targeting aminoglycoside-based adjuvants
Schweizer, Frank
Future Medicinal Chemistry (2019), 11 (13), 1519-1522CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
A review. This article discusses about development and discovery of current strategies to enhance uptake of antibiotics into Gram-neg. bacteria such as carbapenem resistant Pseudomonas aeruginosa, carbapenem resistant Acinetobacter baumannii and carbapenem resistant Enterobacteriaceae using nonribosome targeting aminoglycoside based adjuvants which cause threat to human health.
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Raulston, J. E. and Montie, T. C. (1989) Early Cell Envelope Alterations by Tobramycin Associated with Its Lethal Action on Pseudomonas Aeruginosa. Microbiology 135, 3023– 3034, DOI: 10.1099/00221287-135-11-3023
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Early cell envelope alterations by tobramycin associated with its lethal action on Pseudomonas aeruginosa
Raulston, Jane E.; Montie, Thomas C.
Journal of General Microbiology (1989), 135 (11), 3023-34CODEN: JGMIAN; ISSN:0022-1287.
The immediate activities of the aminoglycoside antibiotic tobramycin were investigated in P. aeruginosa PAO1. The lethal action of a low concn. of tobramycin (8 μg/mL) occurred rapidly (1-3 min) and was assocd. with leakage of certain cellular components into the supernatant. The presence of Mg at the time of initial exposure protected cells by preventing uptake of tobramycin; however, Mg addn. following a brief exposure did not restore viability. Analyses of supernatant material revealed a rapid 2-fold increase in protein released following tobramycin treatment. A prominent 29 kDa protein obsd. by SDS-PAGE in the released material was identified as the periplasmic β-lactamase. Brief exposure to tobramycin did not result in major morphol. damage or cell lysis as obsd. by transmission electron microscopy, and release of lipopolysaccharide was not a primary event. Although activity at the ribosomal level was obsd. by 2-3 min, leakage was detected after only 1 min. These data indicate that leakage of cellular components, particularly β-lactamase, occurs simultaneously, if not prior to inhibition of protein synthesis by tobramycin.
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Bulitta, J. B., Ly, N. S., Landersdorfer, C. B., Wanigaratne, N. A., Velkov, T., Yadav, R., Oliver, A., Martin, L., Shin, B. S., Forrest, A., and Tsuji, B. T. (2015) Two Mechanisms of Killing of Pseudomonas Aeruginosa by Tobramycin Assessed at Multiple Inocula via Mechanism-Based Modeling. Antimicrob. Agents Chemother. 59, 2315– 2327, DOI: 10.1128/AAC.04099-14
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196
Two mechanisms of killing of Pseudomonas aeruginosa by tobramycin assessed at multiple inocula via mechanism-based modeling
Bulitta, Jurgen B.; Ly, Neang S.; Landersdorfer, Cornelia B.; Wanigaratne, Nicholin A.; Velkov, Tony; Yadav, Rajbharan; Oliver, Antonio; Martin, Lisandra; Shin, Beom Soo; Forrest, Alan; Tsuji, Brian T.
Antimicrobial Agents and Chemotherapy (2015), 59 (4), 2315-2327CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-neg. bacteria remains poorly characterized. Here, the authors developed a novel quant. model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three Pseudomonas aeruginosa strains. At low-intermediate tobramycin concns. (<4 mg/L), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concns. (≥8 mg/L). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 108.9 CFU/mL inoculum than that at the lower inocula. At 1 to 4 mg/L tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be crit. to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quant. model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.
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Yang, X., Goswami, S., Gorityala, B. K., Domalaon, R., Lyu, Y., Kumar, A., Zhanel, G. G., and Schweizer, F. (2017) A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria. J. Med. Chem. 60, 3913– 3932, DOI: 10.1021/acs.jmedchem.7b00156
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197
A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria
Yang, Xuan; Goswami, Sudeep; Gorityala, Bala Kishan; Domalaon, Ronald; Lyu, Yinfeng; Kumar, Ayush; Zhanel, George G.; Schweizer, Frank
Journal of Medicinal Chemistry (2017), 60 (9), 3913-3932CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Drug efflux mechanisms interact synergistically with the outer membrane permeability barrier of Gram-neg. bacteria leading to intrinsic resistance that presents a major challenge for antibiotic drug development. Efflux pump inhibitors (EPIs) which block the efflux of antibiotics synergize antibiotics but the clin. development of EPI/antibiotic combination therapy to treat multidrug-resistant (MDR) Gram-neg. infections has been challenging. This is in part caused by the inefficiency of current EPIs to penetrate the outer membrane and resist efflux. The authors demonstrate that conjugation of a tobramycin (TOB) vector to EPIs like NMP, paroxetine or DBP enhances synergy and efficacy of EPIs in combination with tetracycline antibiotics against MDR Gram-neg. bacteria including Pseudomonas aeruginosa. Besides potentiating tetracycline antibiotics TOB-EPI conjugates can also suppress resistance development to the tetracycline antibiotic minocycline thereby providing a strategy to develop more effective adjuvants to rescue tetracycline antibiotics from resistance in MDR Gram-neg. bacteria.
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Gorityala, B. K., Guchhait, G., Goswami, S., Fernando, D. M., Kumar, A., Zhanel, G. G., and Schweizer, F. (2016) Hybrid Antibiotic Overcomes Resistance in P. Aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux. J. Med. Chem. 59, 8441– 8455, DOI: 10.1021/acs.jmedchem.6b00867
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198
Hybrid Antibiotic Overcomes Resistance in P. aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux
Gorityala, Bala Kishan; Guchhait, Goutam; Goswami, Sudeep; Fernando, Dinesh M.; Kumar, Ayush; Zhanel, George G.; Schweizer, Frank
Journal of Medicinal Chemistry (2016), 59 (18), 8441-8455CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. The authors have discovered a tobramycin-moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concn. (MIC) for the hybrid while moxifloxacin or tobramycin resulted in a 16x- and 512x-fold increase in MIC. Although the hybrid possesses potent activity against MDR P. aeruginosa isolates the activity can be synergized when used in combination with other classes of antibiotics.
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Gorityala, B. K., Guchhait, G., Fernando, D. M., Deo, S., McKenna, S. A., Zhanel, G. G., Kumar, A., and Schweizer, F. (2016) Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas Aeruginosa and Enhance Fluoroquinolone Efficacy. Angew. Chem., Int. Ed. 55, 555– 559, DOI: 10.1002/anie.201508330
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Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy
Gorityala, Bala Kishan; Guchhait, Goutam; Fernando, Dinesh M.; Deo, Soumya; McKenna, Sean A.; Zhanel, George G.; Kumar, Ayush; Schweizer, Frank
Angewandte Chemie, International Edition (2016), 55 (2), 555-559CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β-lactam antibiotics and β-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-neg. pathogens has been challenging. The authors describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are sepd. by a C12 tether, is crit. for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.
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Idowu, T., Ammeter, D., Arthur, G., Zhanel, G. G., and Schweizer, F. (2019) Potentiation of Beta-Lactam Antibiotics and Beta-Lactam/Beta-Lactamase Inhibitor Combinations against MDR and XDR Pseudomonas Aeruginosa Using Non-Ribosomal Tobramycin-Cyclam Conjugates. J. Antimicrob. Chemother. 74, 2640– 2648, DOI: 10.1093/jac/dkz228
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Potentiation of beta-lactam antibiotics and beta-lactam/beta-lactamase inhibitor combinations against MDR and XDR Pseudomonas aeruginosa using non-ribosomal tobramycin-cyclam conjugates
Idowu, Temilolu; Ammeter, Derek; Arthur, Gilbert; Zhanel, George G.; Schweizer, Frank
Journal of Antimicrobial Chemotherapy (2019), 74 (9), 2640-2648CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
Objectives: To develop a multifunctional adjuvantmol. that can rescue β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clin. isolates. Methods: Prepn. of adjuvant was guided by structure-activity relationships, following std. protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold diln. assays. Toxicity was evaluated against porcine erythrocytes, human embryonic kidney (HEK293) cells and liver carcinoma (HepG2) cells via MTS assay. Preliminary in vivo efficacy was evaluated using a Galleria mellonella infection model. Results: Conjugation of tobramycin and cyclam abrogates the ribosomal effects of tobramycin but confers a potent adjuvant property that restores full antibiotic activity of meropenem and aztreonam against carbapenem-resistant P. aeruginosa. Therapeutic levels of susceptibility, as detd. by CLSI susceptibility breakpoints, were attained in several MDR clin. isolates, and time-kill assays revealed a synergistic dose-dependent pharmacodynamic relationship. A triple combination of the adjuvant with ceftazidime/avibactam (approved), aztreonam/avibactam(Phase III) and meropenem/avibactam enhances the efficacies of β-lactam/β-lactamase inhibitors against recalcitrant strains, suggesting rapid access of the combination to their periplasmic targets. The newly developed adjuvants, and their combinations, were non-haemolytic and non-cytotoxic, and preliminary in vivo evaluation in G. mellonella suggests therapeutic potential for the double and triple combinations. Conclusions: Non-ribosomal tobramycin-cyclam conjugate mitigates the effect of OprD/OprF porin loss in P. aeruginosa and potentiates β-lactam/β-lactamase inhibitors against carbapenem-resistant clin. isolates, highlighting the complexity of resistance to β-lactam antibiotics. Our strategy presents an avenue to further preserve the therapeutic utility of β-lactamantibiotics.
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Idowu, T., Zhanel, G. G., and Schweizer, F. (2020) A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas Aeruginosa and Delays Resistance Development. Antimicrob. Agents Chemother. 64, e02055-19 DOI: 10.1128/AAC.02055-19
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202
Saikia, K. and Chaudhary, N. (2018) Interaction of MreB-Derived Antimicrobial Peptides with Membranes. Biochem. Biophys. Res. Commun. 498, 58– 63, DOI: 10.1016/j.bbrc.2018.02.176
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Interaction of MreB-derived antimicrobial peptides with membranes
Saikia, Karabi; Chaudhary, Nitin
Biochemical and Biophysical Research Communications (2018), 498 (1), 58-63CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
Antimicrobial peptides are crit. components of defense systems in living forms. The activity is conferred largely by the selective membrane-permeabilizing ability. In our earlier work, we derived potent antimicrobial peptides from the 9-residue long, N-terminal amphipathic helix of E. coli MreB protein. The peptides display broad-spectrum activity, killing not only Gram-pos. and Gram-neg. bacteria but opportunistic fungus, Candida albicans as well. These results proved that membrane-binding stretches of bacterial proteins could turn out to be self-harming when applied from outside. Here, we studied the membrane-binding and membrane-perturbing potential of these peptides. Steady-state tryptophan fluorescence studies with tryptophan extended peptides, WMreB1-9 and its N-terminal acetylated analog, Ac-WMreB1-9 show preferential binding to neg.-charged liposomes. Both the peptides cause permeabilization of E. coli inner and outer-membranes. Tryptophan-lacking peptides, though permeabilize the outer-membrane efficiently, little permeabilization of the inner-membrane is obsd. These data attest membrane-destabilization as the mechanism of rapid bacterial killing. This study is expected to motivate the research in identifying microbes' self-sequences to combat them.
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Saikia, K., Sravani, Y. D., Ramakrishnan, V., and Chaudhary, N. (2017) Highly Potent Antimicrobial Peptides from N-Terminal Membrane-Binding Region of E. Coli MreB. Sci. Rep. 7, 42994, DOI: 10.1038/srep42994
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Highly potent antimicrobial peptides from N-terminal membrane-binding region of E. coli MreB
Saikia, Karabi; Sravani, Yalavarthi Durga; Ramakrishnan, Vibin; Chaudhary, Nitin
Scientific Reports (2017), 7 (), 42994CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
We selected the 9-residue-long membrane-binding region of Escherichia coli MreB protein. The 9-residue peptide (C-terminal amide) and its N-terminal acetylated analog displayed broad-spectrum activity, killing Gram-neg. bacteria, Gram-pos. bacteria, and fungi. Extension with a tryptophan residue at the N-terminus drastically improved the activity of the peptides with lethal concns. ≤10 μM against all the organisms tested. The tryptophan-extended peptides caused complete killing of C. albicans as well as gentamicin and methicillin resistant S. aureus at 5 μM concn. Lipid-binding studies and electron microscopic analyses of the peptide-treated microbes suggest membrane disruption as the mechanism of killing.
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Falagas, M. E. and Kasiakou, S. K. (2006) Toxicity of Polymyxins: A Systematic Review of the Evidence from Old and Recent Studies. Crit. Care 10, R27– R27, DOI: 10.1186/cc3995
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Vattimo, M. de F. F., Watanabe, M., da Fonseca, C. D., Neiva, L. B. de M., Pessoa, E. A., and Borges, F. T. (2016) Polymyxin B Nephrotoxicity: From Organ to Cell Damage. PLoS One 11, e0161057 DOI: 10.1371/journal.pone.0161057
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Polymyxin B nephrotoxicity: from organ to cell damage
Vattimo, Maria de Fatima Fernandes; Watanabe, Mirian; Dezoti da Fonseca, Cassiane; Neiva, Luciana Barros de Moura; Pessoa, Edson Andrade; Borges, Fernanda Teixeira
PLoS One (2016), 11 (8), e0161057/1-e0161057/17CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
Polymyxins have a long history of dose-limiting toxicity, but the underlying mechanism of polymyxin B-induced nephrotoxicity is unclear. This study investigated the link between the nephrotoxic effects of polymyxin B on renal metabolic functions and mitochondrial morphol. in rats and on the structural integrity of LLC-PK1 cells. Fifteen Wistar rats were divided into two groups: Saline group, rats received 3 mL/kg of 0.9% NaCl i.p. (i.p.) once a day for 5 days; Polymyxin B group, rats received 4 mg/kg/day of polymyxin B i.p. once a day for 5 days. Renal function, renal hemodynamics, oxidative stress, mitochondrial injury and histol. characteristics were assessed. Cell membrane damage was evaluated via lactate dehydrogenase and nitric oxide levels, cell viability, and apoptosis in cells exposed to 12.5 μM, 75 μM and 375 μM polymyxin B. Polymyxin B was immunolocated using Lissamine rhodamine-polymyxin B in LLC-PK1 cells. Polymyxin B administration in rats reduced creatinine clearance and increased renal vascular resistance and oxidative damage. Mitochondrial damage was confirmed by electron microscopy and cytosolic localization of cytochrome c. Histol. anal. revealed tubular dilatation and necrosis in the renal cortex. The redn. in cell viability and the increase in apoptosis, lactate dehydrogenase levels and nitric oxide levels confirmed the cytotoxicity of polymyxin B. The incubation of LLC-PK1 cells resulted in mitochondrial localization of polymyxin B. This study demonstrates that polymyxin B nephrotoxicity is characterized by mitochondrial dysfunction and free radical generation in both LLC-PK1 cells and rat kidneys. These data also provide support for clin. studies on the side effects of polymyxin B.
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Pirri, G., Giuliani, A., Nicoletto, S. F., Pizzuto, L., and Rinaldi, A. C. (2009) Lipopeptides as Anti-Infectives: A Practical Perspective. Cent. Eur. J. Biol. 4, 258– 273, DOI: 10.2478/s11535-009-0031-3
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Lipopeptides as anti-infectives: a practical perspective
Pirri, Giovanna; Giuliani, Andrea; Nicoletto, Silvia Fabiole; Pizzuto, Lorena; Rinaldi, Andrea C.
Central European Journal of Biology (2009), 4 (3), 258-273CODEN: CEJBAW; ISSN:1895-104X. (Springer GmbH)
A review. Lipopeptide antibiotics represent an old class of antibiotics that were discovered over 50 years ago, which includes the old polymyxins but also new entries, such as the recently approved daptomycin. They generally consist of a hydrophilic cyclic peptide portion attached to a fatty acid chain which facilitates insertion into the lipid bilayer of bacterial membranes. This review presents an overview of this class of antibiotics, focusing on their therapeutic applications and putting particular emphasis on chem. modifications introduced to improve their activity.
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Vaara, M. and Vaara, T. (1983) Polycations Sensitize Enteric Bacteria to Antibiotics. Antimicrob. Agents Chemother. 24, 107– 113, DOI: 10.1128/AAC.24.1.107
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207
Polycations sensitize enteric bacteria to antibiotics
Vaara, Martti; Vaara, Timo
Antimicrobial Agents and Chemotherapy (1983), 24 (1), 107-13CODEN: AMACCQ; ISSN:0066-4804.
Polymyxin B nonapeptide, a polymyxin B deriv. which lacks the fatty acyl part and the bactericidal activity of polymyxin, sensitized smooth encapsulated Escherichia coli (O18:K1) and smooth Salmonella typhimurium to hydrophobic antibiotics (novobiocin, fusidic acid, erythromycin, clindamycin, nafcillin, and cloxacillin). The polymyxin B nonapeptide-treated bacteria were as sensitive to these antibiotics as were deep rough mutants. A lysine polymer with 20 lysine residues (lysine20) had a largely similar effect. Larger lysine polymers and the protamine salmine were bactericidal but, at sublethal concns., sensitized the strains to the above antibiotics, whereas lysine4, streptomycin, cytochrome c, lysozyme, and the polyamines cadaverine, spermidine, and spermine had neither bactericidal nor sensitizing activity.
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Vaara, M. and Vaara, T. (1983) Sensitization of Gram-Negative Bacteria to Antibiotics and Complement by a Nontoxic Oligopeptide. Nature 303, 526– 528, DOI: 10.1038/303526a0
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208
Sensitization of Gram-negative bacteria to antibiotics and complement by a nontoxic oligopeptide
Vaara, Martti; Vaara, Timo
Nature (London, United Kingdom) (1983), 303 (5917), 526-8CODEN: NATUAS; ISSN:0028-0836.
The polymyxin mol. was modified to obtain a compd. that would act to disorganize the bacterial outer membrane and thus make the membrane more permeable to antibiotics and more vulnerable to attack by the complement cascade. Polymyxin B nonapeptide (PMBN), produced from polymyxin B by the action of ficin, at concns. of ≥0.3 μg/mL caused sensitization of Escherichia coli to hydrophobic antibiotics. In addn., similar concns. of PMBN sensitized the E. coli strain to the bactericidal action of both 30 and 10% guinea pig serum. When the serum was absorbed in the cold to remove the possible natural antibodies against the surface structures of the E. coli strain, it lost most of its PMBN-dependent bactericidal activity. Apparently complement, PMBN, and antibodies are all essential components in the bactericidal system, although normal serum suffices as the antibody source.
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Keirstead, N. D., Wagoner, M. P., Bentley, P., Blais, M., Brown, C., Cheatham, L., Ciaccio, P., Dragan, Y., Ferguson, D., Fikes, J. (2014) Early Prediction of Polymyxin-Induced Nephrotoxicity with next-Generation Urinary Kidney Injury Biomarkers. Toxicol. Sci. 137, 278– 291, DOI: 10.1093/toxsci/kft247
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209
Early Prediction of Polymyxin-Induced Nephrotoxicity With Next-Generation Urinary Kidney Injury Biomarkers
Keirstead, Natalie D.; Wagoner, Matthew P.; Bentley, Patricia; Blais, Marie; Brown, Crystal; Cheatham, Letitia; Ciaccio, Paul; Dragan, Yvonne; Ferguson, Douglas; Fikes, Jim; Galvin, Melanie; Gupta, Anshul; Hale, Michael; Johnson, Nakpangi; Luo, Wenli; McGrath, Frank; Pietras, Mark; Price, Sally; Sathe, Abhishek G.; Sasaki, Jennifer C.; Snow, Debra; Walsky, Robert L.; Kern, Gunther
Toxicological Sciences (2014), 137 (2), 278-291CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
Despite six decades of clin. experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of std. of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) deriv. with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathol. and biomarker anal. of PMBN, an important test of the hypothesis that fatty acid modifications and charge redns. in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathol. injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clin. stds. of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathol. evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.
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Danner, R. L., Joiner, K. A., Rubin, M., Patterson, W. H., Johnson, N., Ayers, K. M., and Parrillo, J. E. (1989) Purification, Toxicity, and Antiendotoxin Activity of Polymyxin B Nonapeptide. Antimicrob. Agents Chemother. 33, 1428– 1434, DOI: 10.1128/AAC.33.9.1428
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Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide
Danner, Robert L.; Joiner, Keith A.; Rubin, Marc; Patterson, William H.; Johnson, Nelson; Ayers, Kenneth M.; Parrillo, Joseph E.
Antimicrobial Agents and Chemotherapy (1989), 33 (9), 1428-34CODEN: AMACCQ; ISSN:0066-4804.
In expts. with lab. animals, polymyxin B nonapeptide (1:5 or 3 mg/kg) did not exhibit the neuromuscular blocking, neurotoxic, or nephrotoxic effects that were obsd. with polymyxin B sulfate. Both polymyxin B and polymyxin B nonapeptide inhibited lipopolysaccharide-induced neutrophil priming in a concn.-dependent manner, but the parent compd., polymyxin B, was 63 times more effective on a wt. basis. The inhibitory activity of both compds., however, diminished rapidly when they were added after the start of the lipopolysaccharide-neutrophil incubation. Thus, polymyxin B nonapeptide is less toxic than polymyxin B and, at the doses tested, lacks the neurotoxicity and nephrotoxicity of the parent compd. Polymyxin B nonapeptide retains the antiendotoxin activity of polymyxin B but is much less potent. These compds. block an early step in the neutrophil priming process, possibly lipopolysaccharide attachment to or insertion into the neutrophil membrane.
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Vaara, M. (2019) Polymyxin Derivatives That Sensitize Gram-Negative Bacteria to Other Antibiotics. Molecules 24, 249, DOI: 10.3390/molecules24020249
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Polymyxin derivatives that sensitize gram-negative bacteria to other antibiotics
Vaara, Martti
Molecules (2019), 24 (2), 249/1-249/15CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-neg. bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clin. use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-neg. bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivs. that are less toxic and/or more effective at tolerable doses are currently under preclin. development and their properties have recently been described in several extensive reviews. Other derivs. lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized "permeabilizer" derivs., i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compd. that recently successfully passed the clin. phase 1. Also, a few other permeabilizer compds. are brought up.
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Recacha, E., Machuca, J., Diaz de Alba, P., Ramos-Guelfo, M., Docobo-Perez, F., Rodriguez-Beltran, J., Blazquez, J., Pascual, A., and Rodriguez-Martinez, J. M. (2017) Quinolone Resistance Reversion by Targeting the SOS Response. mBio 8, e00971-17, DOI: 10.1128/mBio.00971-17
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Ojha, D. and Patil, K. N. (2019) P-Coumaric Acid Inhibits the Listeria Monocytogenes RecA Protein Functions and SOS Response: An Antimicrobial Target. Biochem. Biophys. Res. Commun. 517, 655– 661, DOI: 10.1016/j.bbrc.2019.07.093
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p-Coumaric acid inhibits the Listeria monocytogenes RecA protein functions and SOS response: An antimicrobial target
Ojha, Debika; Patil, K. Neelakanteshwar
Biochemical and Biophysical Research Communications (2019), 517 (4), 655-661CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
Bacterial RecA plays an important role in the evaluation of antibiotic resistance via stress-induced DNA repair mechanism; SOS response. Accordingly, RecA became an important therapeutic target against antimicrobial resistance. Small mol. inhibitors of RecA may prevent adaptation of antibiotic resistance mutations and the emergence of antimicrobial resistance. In our study, we obsd. that phenolic compd. p-Coumaric acid as potent RecA inhibitor. It inhibited RecA driven biochem. activities in vitro such as ssDNA binding, strand exchange, ATP hydrolysis and RecA coprotease activity of E. coli and L. monocytogenes RecA proteins. The mechanism underlying such inhibitory action of p-Coumaric acid involves its ability to interfere with the DNA binding domain of RecA protein. p-Coumaric acid also potentiates the activity of ciprofloxacin by inhibiting drastic cell survival of L. monocytogenes as well as filamentation process; the bacteria defensive mechanism in response to DNA damage. Addnl., it also blocked the ciprofloxacin induced RecA expression leading to suppression of SOS response in L. monocytogenes. These findings revealed that p-Coumaric acid is a potent RecA inhibitor, and can be used as an adjuvant to the existing antibiotics which not only enhance the shelf-life but also slow down the emergence of antibiotic resistance in bacteria.
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Crane, J. K., Cheema, M. B., Olyer, M. A., and Sutton, M. D. (2018) Zinc Blockade of SOS Response Inhibits Horizontal Transfer of Antibiotic Resistance Genes in Enteric Bacteria. Front. Cell. Infect. Microbiol. 8, 410, DOI: 10.3389/fcimb.2018.00410
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Zinc blockade of SOS response inhibits horizontal transfer of antibiotic resistance genes in enteric bacteria
Crane, John K.; Cheema, Muhammad B.; Olyer, Michael A.; Sutton, Mark D.
Frontiers in Cellular and Infection Microbiology (2018), 8 (), 410CODEN: FCIMAB; ISSN:2235-2988. (Frontiers Media S.A.)
The SOS response is a conserved response to DNA damage that is found in Gram-neg. and Gram-pos. bacteria. When DNA damage is sustained and severe, activation of error-prone DNA polymerases can induce a higher mutation rate than is normally obsd., which is called the SOS mutator phenotype or hypermutation. We previously showed that zinc blocked the hypermutation response induced by quinolone antibiotics and mitomycin C in Escherichia coli and Klebsiella pneumoniae. In this study, we demonstrate that zinc blocks the SOS-induced development of chloramphenicol resistance in Enterobacter cloacae. Zinc also blocked the transfer of an extended spectrum beta-lactamase (ESBL) gene from Enterobacter to a susceptible E. coli strain. A zinc ionophore, zinc pyrithione, was ∼100-fold more potent than zinc salts in inhibition of ciprofloxacin-induced hypermutation in E. cloacae. Other divalent metals, such as iron and manganese, failed to inhibit these responses. Electrophoretic mobility shift assays (EMSAs) revealed that zinc, but not iron or manganese, blocked the ability of the E. coli RecA protein to bind to single-stranded DNA, an important early step in the recognition of DNA damage in enteric bacteria. This suggests a mechanism for zinc's inhibitory effects on bacterial SOS responses, including hypermutation.
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Xue, J., Moyer, A., Peng, B., Wu, J., Hannafon, B. N., and Ding, W.-Q. (2014) Chloroquine Is a Zinc Ionophore. PLoS One 9, e109180 DOI: 10.1371/journal.pone.0109180
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Chloroquine is a zinc ionophore
Xue, Jing; Moyer, Amanda; Peng, Bing; Wu, Jinchang; Hannafon, Bethany N.; Ding, Wei-Qun
PLoS One (2014), 9 (10), e109180/1-e109180/6, 6 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
Chloroquine is an established antimalarial agent that has been recently tested in clin. trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780). Chloroquine enhanced zinc uptake by A2780 cells in a concn.-dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compd., indicating the specificity of the zinc uptake. Furthermore, addn. of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examn. of intracellular zinc distribution demonstrated that free zinc ions are more concd. in the lysosomes after addn. of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine's cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine's anticancer activity.
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Mo, C. Y., Culyba, M. J., Selwood, T., Kubiak, J. M., Hostetler, Z. M., Jurewicz, A. J., Keller, P. M., Pope, A. J., Quinn, A., Schneck, J., Widdowson, K. L., and Kohli, R. M. (2018) Inhibitors of LexA Autoproteolysis and the Bacterial SOS Response Discovered by an Academic-Industry Partnership. ACS Infect. Dis. 4, 349– 359, DOI: 10.1021/acsinfecdis.7b00122
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Inhibitors of LexA Autoproteolysis and the Bacterial SOS Response Discovered by an Academic-Industry Partnership
Mo, Charlie Y.; Culyba, Matthew J.; Selwood, Trevor; Kubiak, Jeffrey M.; Hostetler, Zachary M.; Jurewicz, Anthony J.; Keller, Paul M.; Pope, Andrew J.; Quinn, Amy; Schneck, Jessica; Widdowson, Katherine L.; Kohli, Rahul M.
ACS Infectious Diseases (2018), 4 (3), 349-359CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
The RecA/LexA axis of the bacterial DNA damage (SOS) response is a promising, yet nontraditional, drug target. The SOS response is initiated upon genotoxic stress, when RecA, a DNA damage sensor, induces LexA, the SOS repressor, to undergo autoproteolysis, thereby derepressing downstream genes that can mediate DNA repair and accelerate mutagenesis. As genetic inhibition of the SOS response sensitizes bacteria to DNA damaging antibiotics and decreases acquired resistance, inhibitors of the RecA/LexA axis could potentiate our current antibiotic arsenal. Compds. targeting RecA, which has many mammalian homologues, have been reported; however, small-mols. targeting LexA autoproteolysis, a reaction unique to the prokaryotic SOS response, have remained elusive. Here, we describe the logistics and accomplishments of an academic-industry partnership formed to pursue inhibitors against the RecA/LexA axis. A novel fluorescence polarization assay reporting on RecA-induced self-cleavage of LexA enabled the screening of 1.8 million compds. Follow-up studies on select leads show distinct activity patterns in orthogonal assays, including several with activity in cell-based assays reporting on SOS activation. Mechanistic assays demonstrate that we have identified first-in-class small mols. that specifically target the LexA autoproteolysis step in SOS activation. Our efforts establish a realistic example for navigating academic-industry partnerships in pursuit of anti-infective drugs and offer starting points for dedicated lead optimization of SOS inhibitors that could act as adjuvants for current antibiotics.
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Lim, C. S. Q., Ha, K. P., Clarke, R. S., Gavin, L.-A., Cook, D. T., Hutton, J. A., Sutherell, C. L., Edwards, A. M., Evans, L. E., Tate, E. W., and Lanyon-Hogg, T. (2019) Identification of a Potent Small-Molecule Inhibitor of Bacterial DNA Repair That Potentiates Quinolone Antibiotic Activity in Methicillin-Resistant Staphylococcus Aureus. Bioorg. Med. Chem. 27, 114962, DOI: 10.1016/j.bmc.2019.06.025
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Identification of a potent small-molecule inhibitor of bacterial DNA repair that potentiates quinolone antibiotic activity in methicillin-resistant Staphylococcus aureus
Lim, Carine S. Q.; Ha, Kam Pou; Clarke, Rebecca S.; Gavin, Leigh-Anne; Cook, Declan T.; Hutton, Jennie A.; Sutherell, Charlotte L.; Edwards, Andrew M.; Evans, Lindsay E.; Tate, Edward W.; Lanyon-Hogg, Thomas
Bioorganic & Medicinal Chemistry (2019), 27 (20), 114962CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
The global emergence of antibiotic resistance is 1 of the most serious challenges facing modern medicine. There is an urgent need for validation of new drug targets and the development of small mols. with novel mechanisms of action. We therefore sought to inhibit bacterial DNA repair mediated by the AddAB/RecBCD protein complexes as a means to sensitize bacteria to DNA damage caused by the host immune system or quinolone antibiotics. A rational, hypothesis-driven compd. optimization identified I as a cell-active, nanomolar potency compd. I sensitized multidrug-resistant Staphylococcus aureus to the fluoroquinolone antibiotic ciprofloxacin, where resistance results from a point mutation in the fluoroquinolone target, DNA gyrase. Cellular reporter assays indicated I inhibited the bacterial SOS-response to DNA damage, and compd.-functionalized Sepharose successfully pulled-down the AddAB repair complex. This work provides validation of bacterial DNA repair as a novel therapeutic target and delivers I as a tool mol. and starting point for therapeutic development to address the pressing challenge of antibiotic resistance.
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Lee, S., Hinz, A., Bauerle, E., Angermeyer, A., Juhaszova, K., Kaneko, Y., Singh, P. K., and Manoil, C. (2009) Targeting a Bacterial Stress Response to Enhance Antibiotic Action. Proc. Natl. Acad. Sci. U. S. A. 106, 14570– 14575, DOI: 10.1073/pnas.0903619106
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Targeting a bacterial stress response to enhance antibiotic action
Lee, Samuel; Hinz, Aaron; Bauerle, Elizabeth; Angermeyer, Angus; Juhaszova, Katy; Kaneko, Yukihiro; Singh, Pradeep K.; Manoil, Colin
Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (34), 14570-14575, S14570/1-S14570/16CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
This report describes the identification and anal. of a 2-component regulator of Pseudomonas aeruginosa that is a potential aminoglycoside antibiotic combination therapy target. The regulator, AmgRS, was identified in a screen of a comprehensive, defined transposon mutant library for functions whose inactivation increased tobramycin sensitivity. AmgRS mutations enhanced aminoglycoside action against bacteria grown planktonically and in antibiotic tolerant biofilms, against genetically resistant clin. isolates, and in lethal infections of mice. Drugs targeting AmgRS would thus be expected to enhance the clin. efficacy of aminoglycosides. Unexpectedly, the loss of AmgRS reduced virulence in the absence of antibiotics, indicating that its inactivation could protect against infection directly as well as by enhancing aminoglycoside action. Transcription profiling and phenotypic anal. suggested that AmgRS controls an adaptive response to membrane stress, which can be caused by aminoglycoside-induced translational misreading. These results help validate AmgRS as a potential antibiotic combination target for P. aeruginosa and indicate that fundamental stress responses may be a valuable general source of such targets.
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Poole, K., Gilmour, C., Farha, M. A., Mullen, E., Lau, C. H.-F., and Brown, E. D. (2016) Potentiation of Aminoglycoside Activity in Pseudomonas Aeruginosa by Targeting the AmgRS Envelope Stress-Responsive Two-Component System. Antimicrob. Agents Chemother. 60, 3509– 3518, DOI: 10.1128/AAC.03069-15
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Potentiation of aminoglycoside activity in Pseudomonas aeruginosa by targeting the AmgRS envelope stress-responsive two-component system
Poole, Keith; Gilmour, Christie; Farha, Maya A.; Mullen, Erin; Lau, Calvin Ho-Fung; Brown, Eric D.
Antimicrobial Agents and Chemotherapy (2016), 60 (6), 3509-3518CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
A screen for agents that potentiated the activity of paromomycin (PAR), a 4,5-linked aminoglycoside (AG), against wild-type Pseudomonas aeruginosa identified the RNA polymerase inhibitor rifampin (RIF). RIF potentiated addnl. 4,5-linked AGs, such as neomycin and ribostamycin, but not the clin. important 4,6-linked AGs amikacin and gentamicin. Potentiation was absent in a mutant lacking the AmgRS envelope stress response two-component system (TCS), which protects the organism from AG-generated membrane-damaging aberrant polypeptides and, thus, promotes AG resistance, an indication that RIF was acting via this TCS in potentiating 4,5-linked AG activity. Potentiation was also absent in a RIF-resistant RNA polymerase mutant, consistent with its potentiation of AG activity being dependent on RNA polymerase perturbation. PAR-inducible expression of the AmgRS-dependent genes htpX and yccA was reduced by RIF, suggesting that AG activation of this TCS was compromised by this agent. Still, RIF did not compromise the membrane-protective activity of AmgRS, an indication that it impacted some other function of this TCS. RIF potentiated the activities of 4,5-linked AGs against several AG-resistant clin. isolates, in two cases also potentiating the activity of the 4,6-linked AGs. These cases were, in one instance, explained by an obsd. AmgRS-dependent expression of the MexXY multidrug efflux system, which accommodates a range of AGs, with RIF targeting of AmgRS undermining mexXY expression and its promotion of resistance to 4,5- and 4,6-linked AGs. Given this link between AmgRS, MexXY expression, and pan-AG resistance in P. aeruginosa, RIF might be a useful adjuvant in the AG treatment of P. aeruginosa infections.
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Mikalauskas, A., Parkins, M. D., and Poole, K. (2017) Rifampicin Potentiation of Aminoglycoside Activity against Cystic Fibrosis Isolates of Pseudomonas Aeruginosa. J. Antimicrob. Chemother. 72, 3349– 3352, DOI: 10.1093/jac/dkx296
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Rifampicin potentiation of aminoglycoside activity against cystic fibrosis isolates of Pseudomonas aeruginosa
Mikalauskas, Alaya; Parkins, Michael D.; Poole, Keith
Journal of Antimicrobial Chemotherapy (2017), 72 (12), 3349-3352CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
Objectives: Rifampicin potentiates the activity of aminoglycosides (AGs) vs. Pseudomonas aeruginosa by targeting the AmgRS two-component system. In this study we examine the impact of rifampicin on the AG susceptibility of cystic fibrosis (CF) lung isolates of P. aeruginosa and the contribution of AmgRS to AG resistance in these isolates. Methods:amgR deletion derivs. of clin. isolates were constructed using std. gene replacement technol. Susceptibility to AGs ± rifampicin (at 1/2 MIC) was assessed using a serial 2-fold diln. assay. Results: Rifampicin showed a variable ability to potentiate AG activity vs. the CF isolates, enhancing AG susceptibility between 2- and 128-fold. Most strains showed potentiation for at least two AGs, with only a few strains showing no AG potentiation by rifampicin. Notably, loss of amgR increased AG susceptibility although rifampicin potentiation of AG activity was still obsd. in the ΔamgR derivs. Conclusions: AmgRS contributes to AG resistance in CF isolates of P. aeruginosa and rifampicin shows a variable ability to potentiate AG activity against these, highlighting the complexity of AG resistance in such isolates.
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Docquier, J.-D. and Mangani, S. (2018) An Update on Beta-Lactamase Inhibitor Discovery and Development. Drug Resist. Updates 36, 13– 29, DOI: 10.1016/j.drup.2017.11.002
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An update on β-lactamase inhibitor discovery and development
Docquier Jean-Denis; Mangani Stefano
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy (2018), 36 (), 13-29 ISSN:.
Antibiotic resistance, and the emergence of pan-resistant clinical isolates, seriously threatens our capability to treat bacterial diseases, including potentially deadly hospital-acquired infections. This growing issue certainly requires multiple adequate responses, including the improvement of both diagnosis methods and use of antibacterial agents, and obviously the development of novel antibacterial drugs, especially active against Gram-negative pathogens, which represent an urgent medical need. Considering the clinical relevance of both β-lactam antibiotics and β-lactamase-mediated resistance, the discovery and development of combinations including a β-lactamase inhibitor seems to be particularly attractive, despite being extremely challenging due to the enormous diversity, both structurally and mechanistically, of the potential β-lactamase targets. This review will cover the evolution of currently available β-lactamase inhibitors along with the most recent research leading to new β-lactamase inhibitors of potential clinical interest or already in the stage of clinical development.
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Chiem, K., Jani, S., Fuentes, B., Lin, D. L., Rasche, M. E., and Tolmasky, M. E. (2016) Identification of an Inhibitor of the Aminoglycoside 6’-N-Acetyltransferase Type Ib [AAC(6’)-Ib] by Glide Molecular Docking. MedChemComm 7, 184– 189, DOI: 10.1039/C5MD00316D
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Identification of an inhibitor of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] by glide molecular docking
Chiem, Kevin; Jani, Saumya; Fuentes, Brooke; Lin, David L.; Rasche, Madeline E.; Tolmasky, Marcelo E.
MedChemComm (2016), 7 (1), 184-189CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
The aminoglycoside 6'-N-acetyltransferase type Ib, AAC(6')-Ib, confers resistance to clin. relevant aminoglycosides and is the most widely distributed enzyme among AAC(6')-I-producing Gram-neg. pathogens. An alternative to counter the action of this enzyme is the development of inhibitors. Glide is a computational strategy for rapidly docking ligands to protein sites and estg. their binding affinities. We docked a collection of 280 000 compds. from 7 sub-libraries of the Chembridge library as ligands to the aminoglycoside binding site of AAC(6')-Ib. We identified a compd., 1-[3-(2-aminoethyl)benzyl]-3-(piperidin-1-ylmethyl)pyrrolidin-3-ol (compd. 1), that inhibited the acetylation of aminoglycosides in vitro with IC50 values of 39.7 and 34.9 μM when the aminoglycoside substrates assayed were kanamycin A or amikacin, resp. The growth of an amikacin-resistant Acinetobacter baumannii clin. strain was inhibited in the presence of a combination of amikacin and compd. 1.
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Lomovskaya, O., Warren, M. S., Lee, A., Galazzo, J., Fronko, R., Lee, M., Blais, J., Cho, D., Chamberland, S., Renau, T., Leger, R., Hecker, S., Watkins, W., Hoshino, K., Ishida, H., and Lee, V. J. (2001) Identification and Characterization of Inhibitors of Multidrug Resistance Efflux Pumps in Pseudomonas Aeruginosa: Novel Agents for Combination Therapy. Antimicrob. Agents Chemother. 45, 105– 116, DOI: 10.1128/AAC.45.1.105-116.2001
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Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy
Lomovskaya, Olga; Warren, Mark S.; Lee, Angela; Galazzo, Jorge; Fronko, Richard; Lee, May; Blais, Johanne; Cho, Deidre; Chamberland, Suzanne; Renau, Tom; Leger, Roger; Hecker, Scott; Watkins, Will; Hoshino, Kazuki; Ishida, Hiroko; Lee, Ving J.
Antimicrobial Agents and Chemotherapy (2001), 45 (1), 105-116CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
Whole-cell assays were implemented to search for efflux pump inhibitors (EPIs) of the three multidrug resistance efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN) that contribute to fluoroquinolone resistance in clin. isolates of Pseudomonas aeruginosa. Secondary assays were developed to identify lead compds. with exquisite activities as inhibitors. A broad-spectrum EPI which is active against all three known Mex efflux pumps from P. aeruginosa and their close Escherichia coli efflux pump homol. (AcrAB-TolC) was discovered. When this compd., MC-207,110 (I), was used, the intrinsic resistance of P. aeruginosa to fluoroquinolones was decreased significantly (eight-fold for levofloxacin). Acquired resistance due to the overexpression of efflux pumps was also decreased (32- to 64-fold redn. in the MIC of levofloxacin). Similarly, 32- to 64-fold redns. in MICs in the presence of I were obsd. for strains with overexpressed efflux pumps and various target mutations that confer resistance to levofloxacin (e.g., gyrA and parC). We also compared the frequencies of emergence of levofloxacin-resistant variants in the wild-type strain at four times the MIC of levofloxacin (1 μg/mL) when it was used either alone or in combination with EPI. In the case of levofloxacin alone, the frequency was ∼10-7 CFU/mL. In contrast, with an EPI, the frequency was below the level of detection (<10-11). In summary, we have demonstrated that inhibition of efflux pumps (i) decreased the level of intrinsic resistance significantly, (ii) reversed acquired resistance, and (iii) resulted in a decreased frequency of emergence of P. aeruginosa strains that are highly resistant to fluoroquinolones.
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Gupta, S., Cohen, K. A., Winglee, K., Maiga, M., Diarra, B., and Bishai, W. R. (2014) Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium Tuberculosis. Antimicrob. Agents Chemother. 58, 574– 576, DOI: 10.1128/AAC.01462-13
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Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis
Gupta, Shashank; Cohen, Keira A.; Winglee, Kathryn; Maiga, Mamoudou; Diarra, Bassirou; Bishai, William R.
Antimicrobial Agents and Chemotherapy (2014), 58 (1), 574-576, 4 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Drug efflux is an important resistance mechanism in Mycobacterium tuberculosis. We found that verapamil, an efflux inhibitor, profoundly decreases the MIC of bedaquiline and clofazimine to M. tuberculosis by 8- to 16-fold. This exquisite susceptibility was noted among drug-susceptible and drug-resistant clin. isolates. Thus, efflux inhibition is an important sensitizer of bedaquiline and clofazimine, and efflux may emerge as a resistance mechanism to these drugs.
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Singh, M., Jadaun, G. P. S., Ramdas Srivastava, K., Chauhan, V., Mishra, R., Gupta, K., Nair, S., Chauhan, D. S., Sharma, V. D., Venkatesan, K., and Katoch, V. M. (2011) Effect of Efflux Pump Inhibitors on Drug Susceptibility of Ofloxacin Resistant Mycobacterium Tuberculosis Isolates. Indian J. Med. Res. 133, 535– 540
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Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates
Singh, Mradula; Jadaun, G. P. S.; Ramdas; Srivastava, K.; Chauhan, Vipin; Mishra, Ritu; Gupta, Kavita; Nair, Surya; Chauhan, D. S.; Sharma, V. D.; Venkatesan, K.; Katoch, V. M.
Indian Journal of Medical Research (2011), 133 (5), 535-540CODEN: IMIREV; ISSN:0971-5916. (Indian Council of Medical Research)
In drug resistant, esp. multi-drug resistant (MDR) tuberculosis, fluoroquinolones (FQs) are used as second line drugs. However, the incidence of FQ-resistant Mycobacterium tuberculosis is rapidly increasing which may be due to extensive use of FQs in the treatment of various other diseases. The most important known mechanism i.e., gyrA mutation in FQ resistance is not obsd. in a significant proportion of FQ resistant M. tuberculosis isolates suggesting that the resistance may be because of other mechanisms such as an active drug efflux pump. In this study we evaluated the role of the efflux pumps in quinolone resistance by using various inhibitors such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP), 2,4-dinitrophenol (DNP) and verapamil, in clin. isolates of M. tuberculosis. A total of 55 M. tuberculosis clin. isolates [45 ofloxacin (OFL) resistant and 10 ofloxacin sensitive] were tested by Resazurin microtiter assay (REMA) to observe the changes in ofloxacin min. inhibitory concn. (MIC) levels in presence of efflux inhibitors as compared to control (without efflux inhibitor). The MIC levels of OFL showed 2-8 folds redn. in presence of CCCP (16/45; 35.5%), verapamil (24/45; 53.3%) and DNP (21/45; 46.6%) while in case of isolates identified as OFL sensitive these did not show any effect on ofloxacin MICs. In 11 of 45 (24.5%) isolates change in MIC levels was obsd. with all the three inhibitors. Overall 30 (66.6%) isolates had redn. in OFL MIC after treatment with these inhibitors. A total of eight isolates were sequenced for gyrA gene, of which, seven (87.5%) showed known mutations. Of the eight sequenced isolates, seven (87.5%) showed 2 to 8 fold change in MIC in presence of efflux inhibitors. Our findings suggest the involvement of active efflux pumps of both Major Facilitator Super Family (MFS) family (inhibited by CCCP and DNP) and ATP Binding Cassette (ABC) transporters (inhibited by verapamil) in the development of OFL resistance in M. tuberculosis isolates. Epidemiol. significance of these findings needs to be detd. in prospective studies with appropriate no. of samples / isolates.
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Hogg, G. M., Barr, J. G., and Webb, C. H. (1998) In-Vitro Activity of the Combination of Colistin and Rifampicin against Multidrug-Resistant Strains of Acinetobacter Baumannii. J. Antimicrob. Chemother. 41, 494– 450, DOI: 10.1093/jac/41.4.494
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In vitro activity of the combination of colistin and rifampicin against multidrug-resistant strains of Acinetobacter baumannii
Hogg, G. M.; Barr, J. G.; Webb, C. H.
Journal of Antimicrobial Chemotherapy (1998), 41 (4), 494-495CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
The authors have demonstrated, by in vitro studies, the theor. value of the combination of colistin and rifampicin as treatment for patients with infections caused by drug-resistant A. baumannii.
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MacGowan, A. P., Rynn, C., Wootton, M., Bowker, K. E., Holt, H. A., Reeves, D. S. (1999) In Vitro Assessment of Colistin’s Antipseudomonal Antimicrobial Interactions with Other Antibiotics. Clin. Microbiol. Infect. 5, 32– 36, DOI: 10.1111/j.1469-0691.1999.tb00095.x
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In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics
MacGowan, Alasdair P.; Rynn, Caroline; Wootton, Mandy; Bowker, Karen E.; Holt, H. Alan; Reeves, David S.
Clinical Microbiology and Infection (1999), 5 (1), 32-36CODEN: CMINFM; ISSN:1198-743X. (Decker Europe)
The objective of this study was to examine the interactions of colistin (MIC 2 mg/L) at concns. of 0.5 and 5 mg/L with ceftazidime (1 and 75 mg/L, MIC 0.5 mg/L), aztreonam (1 and 30 mg/L, MIC 0.12 mg/L), meropenem (1 and 25 mg/L, MIC 0.03 mg/L), gentamicin (1 and 10 mg/L, MIC 2 mg/L), piperacillin (5 and 100 mg/L, MIC 4 mg/L) and ciprofloxacin (0.25 and 4 mg/L, MIC 1 mg/L) using a representative strain of Pseudomonas aeruginosa isolated from a cystic fibrosis patient. The method used was a bacterial time kill curve with single agents and combinations. Using inocula of 106 CFU/mL, multiple sampling was performed over 6 h and in triplicate. The AUBKC of the time vs. viable count curve, with single agents and combinations of agents, was taken as the endpoint for comparison. For colistin plus ceftazidime, colistin plus aztreonam, colistin plus meropenem and colistin plus ciprofloxacin, the pattern was for all the combinations (high or low concns.) to produce smaller AUBKCs than single agents. In expts. using a bacteriostatic agent such as ceftazidime, the AUBKCs (log CFU/μL per h) for colistin 0.5 mg/L or 5 mg/L alone were 32.3±0.8 or 12.7±0.5, and for ceftazidime 1 mg/L or 75 mg/L alone they were 24.3±1.5 or 20.9±2.7. Combinations of colistin 0.5 mg/L plus either ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 23.8±1.8 or 16.1 mg/L. Combinations of colistin 5 mg/L plus ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 12.2±0.8 or 8.7±1.0. The AUBKCs for colistin 5 mg/L plus 75 mg/L are significantly smaller than those for the single agents, indicating synergy. In expts. using the bactericidal agent ciprofloxacin, the AUBKCs (log CFU/mL per h) for colistin 0.5 mg/L or 5 mg/L alone were 33.6±1.9 or 11.2±2.4, and for ciprofloxacin 0.25 mg/L or 4 mg/L alone they were 32.8±1.3 or 5.0±0.7. Combinations of colistin 0.5 mg/L plus either ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 32.2±0.9 or 4.3±1.4. Combinations of colistin 5 mg/L plus ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 10.7±1.5 or 4.2±0.6. Although combination AUBKCs were smaller than those for single agents, in no case did this reach statistical significance (p<0.05). These studies indicate that addn. of colistin to other antipseudomonal drugs tends to produce smaller AUBKCs and hence greater killing of Pseudomonas aeruginosa than monotherapy.
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Petrosillo, N., Chinello, P., Proietti, M. F., Cecchini, L., Masala, M., Franchi, C., Venditti, M., Esposito, S., and Nicastri, E. (2005) Combined Colistin and Rifampicin Therapy for Carbapenem-Resistant Acinetobacter Baumannii Infections: Clinical Outcome and Adverse Events. Clin. Microbiol. Infect. 11, 682– 683, DOI: 10.1111/j.1469-0691.2005.01198.x
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Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii infections: clinical outcome and adverse events
Petrosillo, N.; Chinello, P.; Proietti, M. F.; Cecchini, L.; Masala, M.; Franchi, C.; Venditti, M.; Esposito, S.; Nicastri, E.
Clinical Microbiology and Infection (2005), 11 (8), 682-683CODEN: CMINFM; ISSN:1198-743X. (Blackwell Publishing Ltd.)
Fourteen critically-ill patients with carbapenem-resistant Acinetobacter baumannii infections (mean age 49 years), in the intensive care units of three urban hospitals in Rome, Italy were studied. Therapy with colistin-rifampicin, and with ampicillin-sulbactam in case of susceptibility to this combination, resulted in microbiol. clearance of carbapenem-resistant A. baumannii infection in nine (64%) of these 14 patients, with limited side-effects.
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Kerrigan, J. E., Ragunath, C., Kandra, L., Gyemant, G., Liptak, A., Janossy, L., Kaplan, J. B., and Ramasubbu, N. (2008) Modeling and Biochemical Analysis of the Activity of Antibiofilm Agent Dispersin B. Acta Biol. Hung. 59, 439– 451, DOI: 10.1556/ABiol.59.2008.4.5
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Modeling and biochemical analysis of the activity of antibiofilm agent Dispersin B
Kerrigan J E; Ragunath C; Kandra Lili; Gyemant Gyongyi; Liptak A; Janossy L; Kaplan J B; Ramasubbu N
Acta biologica Hungarica (2008), 59 (4), 439-51 ISSN:0236-5383.
Bacteria in a biofilm are enmeshed in a self-synthesized extracellular polysaccharide matrix (PGA), which is a linear polymer of beta(1,6)-linked N-acetylglucosamine (GlcNAc) residues. Dispersin B (DspB), a soluble glycoside hydrolase produced by the periodontal pathogen Actinobacillus actinomycetemcomitans degrades PGA. The enzyme DspB is an alpha/beta TIM-barrel protein and belongs to family 20 glycosyl hydrolases members. The enzyme activity of DspB with regard to its substrate specificity towards beta(1,6)-linked GlcNAc polymers and its endo/exo character was investigated through ligand docking and the hydrolysis of synthetic oligosaccharides. Ligand docking analysis suggested that beta(1,6)-linked GlcNAc oligosaccharide bound to the active site better that beta(1,4)-linked GlcNAc oligosaccharide. Our combined results indicate that DspB is an exo-acting enzyme that hydrolyzes beta(1,6)-linked N-acetylglucosamine oligomers.
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Ramasubbu, N., Thomas, L. M., Ragunath, C., and Kaplan, J. B. (2005) Structural Analysis of Dispersin B, a Biofilm-Releasing Glycoside Hydrolase from the Periodontopathogen Actinobacillus Actinomycetemcomitans. J. Mol. Biol. 349, 475– 486, DOI: 10.1016/j.jmb.2005.03.082
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Structural Analysis of Dispersin B, a Biofilm-releasing Glycoside Hydrolase from the Periodontopathogen Actinobacillus actinomycetemcomitans
Ramasubbu, N.; Thomas, L. M.; Ragunath, C.; Kaplan, J. B.
Journal of Molecular Biology (2005), 349 (3), 475-486CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)
Bacteria in a biofilm are enmeshed in a self-synthesized extracellular polysaccharide matrix that holds the bacteria together in a mass and firmly attaches the bacterial mass to the underlying surface. A major component of the extracellular polysaccharide matrix in several phylogenetically diverse bacteria is PGA, a linear polymer of N-acetylglucosamine residues in β(1,6)-linkage. PGA is produced by the Gram-neg. periodontopathogen Actinobacillus actinomycetemcomitans as well as by the Gram-pos. device-assocd. pathogen Staphylococcus epidermidis. We recently reported that A. actinomycetemcomitans produces a sol. glycoside hydrolase named dispersin B, which degrades PGA. Here, we present the crystal structure of dispersin B at 2.0 Å in complex with a glycerol and an acetate ion at the active site. The enzyme crystallizes in the orthorhombic space group C2221 with cell dimensions a=41.02 Å, b=86.13 Å, c=185.77 Å. The core of the enzyme consists a (β/α)8 barrel topol. similar to other β-hexosaminidases but significant differences exist in the arrangement of loops hovering in the vicinity of the active site. The location and interactions of the glycerol and acetate moieties in conjunction with the sequence anal. suggest that dispersin B cleaves β(1,6)-linked N-acetylglucosamine polymer using a catalytic machinery similar to other family 20 hexosaminidases which cleave β(1,4)-linked N-acetylglucosamine residues.
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Brindle, E. R., Miller, D. A., and Stewart, P. S. (2011) Hydrodynamic Deformation and Removal of Staphylococcus Epidermidis Biofilms Treated with Urea, Chlorhexidine, Iron Chloride, or DispersinB. Biotechnol. Bioeng. 108, 2968– 2977, DOI: 10.1002/bit.23245
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Hydrodynamic deformation and removal of Staphylococcus epidermidis biofilms treated with urea, chlorhexidine, iron chloride, or DispersinB
Brindle, Eric R.; Miller, David A.; Stewart, Philip S.
Biotechnology and Bioengineering (2011), 108 (12), 2968-2977CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)
The force-deflection and removal characteristics of bacterial biofilm were measured by two different techniques before and after chem., or enzymic, treatment. The first technique involved time lapse imaging of a biofilm grown in a capillary flow cell and subjected to a brief shear stress challenge imparted through increased fluid flow. Biofilm removal was detd. by calcg. the redn. in biofilm area from quant. anal. of transmission images. The second technique was based on micro-indentation using an at. force microscope. In both cases, biofilms formed by Staphylococcus epidermidis were exposed to buffer (untreated control), urea, chlorhexidine, iron chloride, or DispersinB. In control expts., the biofilm exhibited force-deflection responses that were similar before and after the same treatment. The biofilm structure was stable during the post-treatment shear challenge (1% loss). Biofilms treated with chlorhexidine became less deformable after treatment and no increase in biomass removal was seen during the post-treatment shear challenge (2% loss). In contrast, biofilms treated with urea or DispersinB became more deformable and exhibited significant biofilm loss during the post-treatment flow challenge (71% and 40%, resp.). During the treatment soak phase, biofilms exposed to urea swelled. Biofilms exposed to iron chloride showed little difference from the control other than slight contraction during the treatment soak. These observations suggest the following interpretations: (1) chem. or enzymic treatments, including those that are not frankly antimicrobial, can alter the cohesion of bacterial biofilm; (2) biocidal treatments (e.g., chlorhexidine) do not necessarily weaken the biofilm; and (3) biofilm removal following treatment with agents that make the biofilm more deformable (e.g., urea, DispersinB) depend on interaction between the moving fluid and the biofilm structure. Measurements such as those reported here open the door to development of new technologies for controlling detrimental biofilms by targeting biofilm cohesion rather than killing microorganisms.
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Fernandez-Lopez, R., Machon, C., Longshaw, C. M., Martin, S., Molin, S., Zechner, E. L., Espinosa, M., Lanka, E., and de la Cruz, F. (2005) Unsaturated Fatty Acids Are Inhibitors of Bacterial Conjugation. Microbiology 151, 3517– 3526, DOI: 10.1099/mic.0.28216-0
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Unsaturated fatty acids are inhibitors of bacterial conjugation
Fernandez-Lopez, Raul; Machon, Cristina; Longshaw, Christopher M.; Martin, Steve; Molin, Soren; Zechner, Ellen L.; Espinosa, Manuel; Lanka, Erich; de la Cruz, Fernando
Microbiology (Reading, United Kingdom) (2005), 151 (11), 3517-3526CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
This report describes a high-throughput assay to identify substances that reduce the frequency of conjugation in Gram-neg. bacteria. Bacterial conjugation is largely responsible for the spread of multiple antibiotic resistances in human pathogens. Conjugation inhibitors may provide a means to control the spread of antibiotic resistance. An automated conjugation assay was developed that used plasmid R388 and a lab. strain of Escherichia coli as a model system, and bioluminescence as a reporter for conjugation activity. Frequencies of conjugation could be measured continuously in real time by the amt. of light produced, and thus the effects of inhibitory compds. could be detd. quant. A control assay, run in parallel, allowed elimination of compds. affecting cell growth, plasmid stability or gene expression. The automated conjugation assay was used to screen a database of more than 12 000 microbial exts. known to contain a wide variety of bioactive compds. (the NatChem library). The initial hit rate was 1.4%. From these, 48 exts. contg. active compds. and representing a variety of organisms and extn. conditions were subjected to fractionation (24 fractions per ext.). The 52 most active fractions were subjected to a secondary anal. to det. the range of plasmid inhibition. Plasmids R388, R1 and RP4 were used as representatives of a variety of plasmid transfer systems. Only one fraction (of complex compn.) affected transfer of all three plasmids, while four other fractions were active against two of them. Two sep. compds. were identified from these fractions: linoleic acid and dehydrocrepenynic acid. Downstream anal. showed that the chem. class of unsatd. fatty acids act as true inhibitors of conjugation.
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Perry, J. A., Koteva, K., Verschoor, C. P., Wang, W., Bowdish, D. M. E., and Wright, G. D. (2015) A Macrophage-Stimulating Compound from a Screen of Microbial Natural Products. J. Antibiot. 68, 40– 46, DOI: 10.1038/ja.2014.83
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A macrophage-stimulating compound from a screen of microbial natural products
Perry, Julie A.; Koteva, Kalinka; Verschoor, Chris P.; Wang, Wenliang; Bowdish, Dawn ME; Wright, Gerry D.
Journal of Antibiotics (2015), 68 (1), 40-46CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
Rising rates of antibiotic resistance in bacterial pathogens is a medical crisis of global concern that necessitates the development of new treatment strategies. We have isolated a natural product with macrophage-stimulating activity from a screen of microbially produced bioactive mols. Streptazolin increased bacterial killing and elaboration of immunostimulatory cytokines by macrophages in vitro. Furthermore, we show that streptazolin stimulates the macrophage nuclear factor κB (NF-κB) pathway via phosphatidylinositide 3-kinase (PI3K) signaling, and that the conjugated diene moiety is essential for stimulatory activity. Immunostimulatory mols. like streptazolin represent entries into new treatment paradigms to address the challenge of antibiotic resistance.
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Gonzalez-Bello, C., Rodriguez, D., Pernas, M., Rodriguez, A., and Colchon, E. (2020) Beta-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against Superbugs. J. Med. Chem. 63, 1859, DOI: 10.1021/acs.jmedchem.9b01279
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β-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against Superbugs
Gonzalez-Bello, Concepcion; Rodriguez, Diana; Pernas, Marina; Rodriguez, Angela; Colchon, Esther
Journal of Medicinal Chemistry (2020), 63 (5), 1859-1881CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Infections caused by resistant bacteria are nowadays too common and some pathogens have even become resistant to multiple types of antibiotics, in which cases few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy 'antibiotic + inhibitor of resistance'. These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clin. use. Three main types of compds. have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; and (iii) efflux pump inhibitors. This perspective article is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-neg. bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems and monobactams), by the prodn. of β-lactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.
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Drawz, S. M. and Bonomo, R. A. (2010) Three Decades of β-Lactamase Inhibitors. Clin. Microbiol. Rev. 23, 160– 201, DOI: 10.1128/CMR.00037-09
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Three decades of β-lactamase inhibitors
Drawz, Sarah M.; Bonomo, Robert A.
Clinical Microbiology Reviews (2010), 23 (1), 160-201CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
A review. Since the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clin. practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clin. relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clin. and microbiol. features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compds. and the chem. features of these agents that may contribute to a "second generation" of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.
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Garneau-Tsodikova, S. and Labby, K. J. (2016) Mechanisms of Resistance to Aminoglycoside Antibiotics: Overview and Perspectives. MedChemComm 7, 11– 27, DOI: 10.1039/C5MD00344J
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Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives
Garneau-Tsodikova, Sylvie; Labby, Kristin J.
MedChemComm (2016), 7 (1), 11-27CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
A review. Aminoglycoside (AG) antibiotics are used to treat many Gram-neg. and some Gram-pos. infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small mols. such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clin. prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clin. relevance.
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Li, Y., Green, K. D., Johnson, B. R., and Garneau-Tsodikova, S. (2015) Inhibition of Aminoglycoside Acetyltransferase Resistance Enzymes by Metal Salts. Antimicrob. Agents Chemother. 59, 4148– 4156, DOI: 10.1128/AAC.00885-15
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Inhibition of aminoglycoside acetyltransferase resistance enzymes by metal salts
Li, Yijia; Green, Keith D.; Johnson, Brooke R.; Garneau-Tsodikova, Sylvie
Antimicrobial Agents and Chemotherapy (2015), 59 (7), 4148-4156CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
Aminoglycosides (AGs) are clin. relevant antibiotics used to treat infections caused by both Gram-neg. and Gram-pos. bacteria, as well as Mycobacteria. As with all current antibacterial agents, resistance to AGs is an increasing problem. The most common mechanism of resistance to AGs is the presence of AG-modifying enzymes (AMEs) in bacterial cells, with AG acetyltransferases (AACs) being the most prevalent. Recently, it was discovered that Zn2+ metal ions displayed an inhibitory effect on the resistance enzyme AAC(6')-Ib in Acinetobacter baumannii and Escherichia coli. In this study, we explore a wide array of metal salts (Mg2+, Cr3+, Cr6+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Au3+ with different counter ions) and their inhibitory effect on a large repertoire of AACs [AAC(2')-Ic, AAC(3)-Ia, AAC(3)-Ib, AAC(3)-IV, AAC(6')-Ib', AAC(6')-Ie, AAC(6')-IId, and Eis]. In addn., we det. the MIC values for amikacin and tobramycin in combination with a zinc pyrithione complex in clin. isolates of various bacterial strains (two strains of A. baumannii, three of Enterobacter cloacae, and four of Klebsiella pneumoniae) and one representative of each species purchased from the American Type Culture Collection.
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Lin, D. L., Tran, T., Adams, C., Alam, J. Y., Herron, S. R., and Tolmasky, M. E. (2013) Inhibitors of the Aminoglycoside 6’-N-Acetyltransferase Type Ib [AAC(6’)-Ib] Identified by in Silico Molecular Docking. Bioorg. Med. Chem. Lett. 23, 5694– 5698, DOI: 10.1016/j.bmcl.2013.08.016
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Inhibitors of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] identified by in silico molecular docking
Lin, David L.; Tran, Tung; Adams, Christina; Alam, Jamal Y.; Herron, Steven R.; Tolmasky, Marcelo E.
Bioorganic & Medicinal Chemistry Letters (2013), 23 (20), 5694-5698CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
AAC(6')-Ib is an important aminoglycoside resistance enzyme to target with enzymic inhibitors. An in silico screening approach was used to identify potential inhibitors from the ChemBridge library. Several compds. were identified, of which two of them, 4-[(2-{[1-(3-methylphenyl)-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene]methyl}phenoxy)methyl]benzoic acid and 2-{5-[(4,6-dioxo-1,3-diphenyl-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid, showed micromolar activity in inhibiting acetylation of kanamycin A. These compds. are predicted to bind the aminoglycoside binding site of AAC(6')-Ib and exhibited competitive inhibition against kanamycin A.
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Green, K. D., Chen, W., and Garneau-Tsodikova, S. (2012) Identification and Characterization of Inhibitors of the Aminoglycoside Resistance Acetyltransferase Eis from Mycobacterium Tuberculosis. ChemMedChem 7, 73– 77, DOI: 10.1002/cmdc.201100332
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Identification and Characterization of Inhibitors of the Aminoglycoside Resistance Acetyltransferase Eis from Mycobacterium tuberculosis
Green, Keith D.; Chen, Wenjing; Garneau-Tsodikova, Sylvie
ChemMedChem (2012), 7 (1), 73-77CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
Inhibitors of aminoglycoside resistance acetyltransferase Eis from Mycobacterium tuberculosis were identified by high throughput screening.
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Li, X.-Z., Plesiat, P., and Nikaido, H. (2015) The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria. Clin. Microbiol. Rev. 28, 337– 418, DOI: 10.1128/CMR.00117-14
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The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria
Li, Xian-Zhi; Plesiat, Patrick; Nikaido, Hiroshi
Clinical Microbiology Reviews (2015), 28 (2), 337-418CODEN: CMIREX; ISSN:1098-6618. (American Society for Microbiology)
The global emergence of multidrug-resistant Gram-neg. bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clin. relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Addnl., efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technol. advances have allowed for an in-depth understanding of the structural and biochem. basis, substrate profiles, mol. regulation, and inhibition of MDR pumps. However, the development of clin. useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clin. significance, together with methodol. considerations for the characterization of MDR pumps.
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Sharma, A., Gupta, V. K., and Pathania, R. (2019) Efflux Pump Inhibitors for Bacterial Pathogens: From Bench to Bedside. Indian J. Med. Res. 149, 129– 145, DOI: 10.4103/ijmr.IJMR_2079_17
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Efflux pump inhibitors for bacterial pathogens: From bench to bedside
Sharma, Atin; Gupta, Vivek Kumar; Pathania, Ranjana
Indian Journal of Medical Research (2019), 149 (2), 129-145CODEN: IMIREV ISSN:. (Medknow Publications)
A review. With the advent of antibiotics, bacterial infections were supposed to be a thing of past. However, this instead led to the selection and evolution of bacteria with mechanisms to counter the action of antibiotics. Antibiotic efflux is one of the major mechanisms, whereby bacteria pump out the antibiotics from their cellular interior to the external environment using special transporter proteins called efflux pumps. Inhibiting these pumps seems to be an attractive strategy at a time when novel antibiotic supplies are dwindling. Mols. capable of inhibiting these pumps, known as efflux pump inhibitors (EPIs), have been viewed as potential therapeutic agents that can rejuvenate the activity of antibiotics that are no longer effective against bacterial pathogens. EPIs follow some general mechanisms of efflux inhibition and are derived from various natural as well as synthetic sources. This review focuses on EPIs and identifies the challenges that have kept these futuristic therapeutics away from the com. realm so far.
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Handzlik, J., Matys, A., and Kieć-Kononowicz, K. (2013) Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. Aureus. Antibiotics 2, 28– 45, DOI: 10.3390/antibiotics2010028
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Recent advances in multi-drug resistance (MDR) efflux pump inhibitors of Gram-positive bacteria S. aureus
Handzlik, Jadwiga; Matys, Anna; Kiec-Kononowicz, Katarzyna
Antibiotics (Basel, Switzerland) (2013), 2 (1), 28-45CODEN: ABSNC4; ISSN:2079-6382. (MDPI AG)
A review. The paper focuses on recent achievements in the search for new chem. compds. able to inhibit multidrug resistance (MDR) mechanisms in Gram-pos. pathogens. An anal. of the results of the search for new efflux pump inhibitors (EPIs) for Gram-pos. bacteria, which have been performed over the last decade, indicates that almost all efforts are focused on the NorA (MFS) efflux pump in S. aureus. Considering the chem. structures of the NorA EPIs that have been identified, it can be obsd. that the most active agents belong to the families of compds. possessing conjugated double bonds, e.g., chalcones, piperine-like compds., N-cinnamoylphenalkylamides or citral amide derivs. Indole-, dihydronaphthyl-, 2-chloro-5-bromo-phenyl- or piperidine moieties seem to be profitable for the EPI properties, as well. These results, together with an increasing knowledge about a variety of efflux pumps that are involved in MDR of Gram-pos. pathogens underline that further search for new EPIs should pay more attention to develop MDR efflux protein targets, including SMR, MATE, ABC or other members of the MFS family.
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Spengler, G., Kincses, A., Gajdacs, M., and Amaral, L. (2017) New Roads Leading to Old Destinations: Efflux Pumps as Targets to Reverse Multidrug Resistance in Bacteria. Molecules 22, 468, DOI: 10.3390/molecules22030468
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New roads leading to old destinations: efflux pumps as targets to reverse multidrug resistance in bacteria
Spengler, Gabriella; Kincses, Annamaria; Gajdacs, Mario; Amaral, Leonard
Molecules (2017), 22 (3), 468/1-468/25CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
A review. Multidrug resistance (MDR) has appeared in response to selective pressures resulting from the incorrect use of antibiotics and other antimicrobials. This inappropriate application and mismanagement of antibiotics have led to serious problems in the therapy of infectious diseases. Bacteria can develop resistance by various mechanisms and 1 of the most important factors resulting in MDR is efflux pump-mediated resistance. Because of the importance of the efflux-related multidrug resistance the development of new therapeutic approaches aiming to inhibit bacterial efflux pumps is a promising way to combat bacteria having over-expressed MDR efflux systems. The definition of an efflux pump inhibitor (EPI) includes the ability to render the bacterium increasingly more sensitive to a given antibiotic or even reverse the multidrug resistant phenotype. In the recent years numerous EPIs have been developed, although so far their clin. application has not yet been achieved due to their in vivo toxicity and side effects. We aim to give a short overview of efflux-mediated resistance in bacteria, EPI compds. of plant and synthetic origin, and the possible methods to investigate and screen EPI compds. in bacterial systems.
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Song, L. and Wu, X. (2016) Development of Efflux Pump Inhibitors in Antituberculosis Therapy. Int. J. Antimicrob. Agents 47, 421– 429, DOI: 10.1016/j.ijantimicag.2016.04.007
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Development of efflux pump inhibitors in antituberculosis therapy
Song, Lele; Wu, Xueqiong
International Journal of Antimicrobial Agents (2016), 47 (6), 421-429CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
Resistance and tolerance to antituberculosis (anti-TB) drugs, esp. the first-line drugs, has become a serious problem in anti-TB therapy. Efflux of antimicrobial agents via bacterial efflux pumps is one of the main reasons for drug resistance. Efflux pump inhibitors (EPIs) bind to efflux pumps to inhibit drug efflux and thus enhance the drug effect and reduce drug resistance. Studies on EPIs targeting the efflux pumps of Mycobacterium tuberculosis (Mtb) help to understand Mtb resistance and to identify the potential drug target and are of significance in guiding the development of new anti-TB drugs and optimal combinations. Currently, there are many potential EPIs under study, but none of them has been used clin. for anti-TB therapy. In this article, we will provide an overview on the current development of EPIs targeting the efflux pumps of Mtb and discuss their potential clin. applications.
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Schillaci, D., Spano, V., Parrino, B., Carbone, A., Montalbano, A., Barraja, P., Diana, P., Cirrincione, G., and Cascioferro, S. (2017) Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms. J. Med. Chem. 60, 8268– 8297, DOI: 10.1021/acs.jmedchem.7b00215
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Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms
Schillaci, Domenico; Spano, Virginia; Parrino, Barbara; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo; Cascioferro, Stella
Journal of Medicinal Chemistry (2017), 60 (20), 8268-8297CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chem. agents that target the most common mechanisms of antibiotic resistance such as enzymic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here the authors assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. The authors also discuss the potential clin. application of chem. inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymic inhibitors, such as the derivs. of the β-lactamase inhibitor avibactam, are closer to the clinic than other mols. For example, MK-7655, in combination with imipenem, is in clin. development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addn., other mols. targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.
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Soucy, S. M., Huang, J., and Gogarten, J. P. (2015) Horizontal Gene Transfer: Building the Web of Life. Nat. Rev. Genet. 16, 472– 482, DOI: 10.1038/nrg3962
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Horizontal gene transfer: building the web of life
Soucy, Shannon M.; Huang, Jinling; Gogarten, Johann Peter
Nature Reviews Genetics (2015), 16 (8), 472-482CODEN: NRGAAM; ISSN:1471-0056. (Nature Publishing Group)
A review. Horizontal gene transfer (HGT) is the sharing of genetic material between organisms that are not in a parent-offspring relationship. HGT is a widely recognized mechanism for adaptation in bacteria and archaea. Microbial antibiotic resistance and pathogenicity are often assocd. with HGT, but the scope of HGT extends far beyond disease-causing organisms. In this review, we describe how HGT has shaped the web of life using examples of HGT among prokaryotes, between prokaryotes and eukaryotes, and even between multicellular eukaryotes. We discuss replacement and additive HGT, the proposed mechanisms of HGT, selective forces that influence HGT, and the evolutionary impact of HGT on ancestral populations and existing populations such as the human microbiome.
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Graf, F. E., Palm, M., Warringer, J., and Farewell, A. (2019) Inhibiting Conjugation as a Tool in the Fight against Antibiotic Resistance. Drug Dev. Res. 80, 19– 23, DOI: 10.1002/ddr.21457
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Inhibiting conjugation as a tool in the fight against antibiotic resistance
Graf, Fabrice E.; Palm, Martin; Warringer, Jonas; Farewell, Anne
Drug Development Research (2019), 80 (1), 19-23CODEN: DDREDK; ISSN:0272-4391. (Wiley-Liss, Inc.)
Hit, Lead & Candidate Discovery Antibiotic resistance, esp. in gram-neg. bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addn. to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.
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Cabezón, E., de la Cruz, F., and Arechaga, I. (2017) Conjugation Inhibitors and Their Potential Use to Prevent Dissemination of Antibiotic Resistance Genes in Bacteria. Front. Microbiol. 8, 2329, DOI: 10.3389/fmicb.2017.02329
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Conjugation Inhibitors and Their Potential Use to Prevent Dissemination of Antibiotic Resistance Genes in Bacteria
Cabezon Elena; de la Cruz Fernando; Arechaga Ignacio
Frontiers in microbiology (2017), 8 (), 2329 ISSN:1664-302X.
Antibiotic resistance has become one of the most challenging problems in health care. Bacteria conjugation is one of the main mechanisms whereby bacteria become resistant to antibiotics. Therefore, the search for specific conjugation inhibitors (COINs) is of interest in the fight against the spread of antibiotic resistances in a variety of laboratory and natural environments. Several compounds, discovered as COINs, are promising candidates in the fight against plasmid dissemination. In this review, we survey the effectiveness and toxicity of the most relevant compounds. Particular emphasis has been placed on unsaturated fatty acid derivatives, as they have been shown to be efficient in preventing plasmid invasiveness in bacterial populations. Biochemical and structural studies have provided insights concerning their potential molecular targets and inhibitory mechanisms. These findings open a new avenue in the search of new and more effective synthetic inhibitors. In this pursuit, the use of structure-based drug design methods will be of great importance for the screening of ligands and binding sites of putative targets.
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Getino, M., Sanabria-Rios, D. J., Fernandez-Lopez, R., Campos-Gomez, J., Sanchez-Lopez, J. M., Fernandez, A., Carballeira, N. M., and de la Cruz, F. (2015) Synthetic Fatty Acids Prevent Plasmid-Mediated Horizontal Gene Transfer. mBio 6, e01032-15 DOI: 10.1128/mBio.01032-15
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Zhu, L. and Lau, G. W. (2011) Inhibition of Competence Development, Horizontal Gene Transfer and Virulence in Streptococcus Pneumoniae by a Modified Competence Stimulating Peptide. PLoS Pathog. 7, e1002241 DOI: 10.1371/journal.ppat.1002241
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Inhibition of competence development, horizontal gene transfer and virulence in Streptococcus pneumoniae by a modified competence stimulating peptide
Zhu, Luchang; Lau, Gee W.
PLoS Pathogens (2011), 7 (9), e1002241CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
Competence stimulating peptide (CSP) is a 17-amino acid peptide pheromone secreted by Streptococcus pneumoniae. Upon binding of CSP to its membrane-assocd. receptor kinase ComD, a cascade of signaling events is initiated, leading to activation of the competence regulon by the response regulator ComE. Genes encoding proteins that are involved in DNA uptake and transformation, as well as virulence, are upregulated. Previous studies have shown that disruption of key components in the competence regulon inhibits DNA transformation and attenuates virulence. Thus, synthetic analogs that competitively inhibit CSPs may serve as attractive drugs to control pneumococcal infection and to reduce horizontal gene transfer during infection. The authors performed amino acid substitutions on conserved amino acid residues of CSP1 in an effort to disable DNA transformation and to attenuate the virulence of S. pneumoniae. One of the mutated peptides, CSP1-E1A, inhibited development of competence in DNA transformation by outcompeting CSP1 in time and concn.-dependent manners. CSP1-E1A reduced the expression of pneumococcal virulence factors choline binding protein D (CbpD) and autolysin A (LytA) in vitro, and significantly reduced mouse mortality after lung infection. Furthermore, CSP1-E1A attenuated the acquisition of an antibiotic resistance gene and a capsule gene in vivo. Finally, the authors demonstrated that the strategy of using a peptide inhibitor is applicable to other CSP subtype, including CSP2. CSP1-E1A and CSP2-E1A were able to cross inhibit the induction of competence and DNA transformation in pneumococcal strains with incompatible ComD subtypes. These results demonstrate the applicability of generating competitive analogs of CSPs as drugs to control horizontal transfer of antibiotic resistance and virulence genes, and to attenuate virulence during infection by S. pneumoniae.
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Shaffer, C. L., Good, J. A. D., Kumar, S., Krishnan, K. S., Gaddy, J. A., Loh, J. T., Chappell, J., Almqvist, F., Cover, T. L., and Hadjifrangiskou, M. (2016) Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens. mBio 7, e00221-16 DOI: 10.1128/mBio.00221-16
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Grassi, L., Maisetta, G., Esin, S., and Batoni, G. (2017) Combination Strategies to Enhance the Efficacy of Antimicrobial Peptides against Bacterial Biofilms. Front. Microbiol. 8, 2409, DOI: 10.3389/fmicb.2017.02409
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Combination Strategies to Enhance the Efficacy of Antimicrobial Peptides against Bacterial Biofilms
Grassi Lucia; Maisetta Giuseppantonio; Esin Semih; Batoni Giovanna
Frontiers in microbiology (2017), 8 (), 2409 ISSN:1664-302X.
The great clinical significance of biofilm-associated infections and their inherent recalcitrance to antibiotic treatment urgently demand the development of novel antibiofilm strategies. In this regard, antimicrobial peptides (AMPs) are increasingly recognized as a promising template for the development of antibiofilm drugs. Indeed, owing to their main mechanism of action, which relies on the permeabilization of bacterial membranes, AMPs exhibit a strong antimicrobial activity also against multidrug-resistant bacteria and slow-growing or dormant biofilm-forming cells and are less prone to induce resistance compared to current antibiotics. Furthermore, the antimicrobial potency of AMPs can be highly increased by combining them with conventional (antibiotics) as well as unconventional bioactive molecules. Combination treatments appear particularly attractive in the case of biofilms since the heterogeneous nature of these microbial communities requires to target cells in different metabolic states (e.g., actively growing cells, dormant cells) and environmental conditions (e.g., acidic pH, lack of oxygen or nutrients). Therefore, the combination of different bioactive molecules acting against distinct biofilm components has the potential to facilitate biofilm control and/or eradication. The aim of this review is to highlight the most promising combination strategies developed so far to enhance the therapeutic potential of AMPs against bacterial biofilms. The rationale behind and beneficial outcomes of using AMPs in combination with conventional antibiotics, compounds capable of disaggregating the extracellular matrix, inhibitors of signaling pathways involved in biofilm formation (i.e., quorum sensing), and other peptide-based molecules will be presented and discussed.
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Roy, R., Tiwari, M., Donelli, G., and Tiwari, V. (2018) Strategies for Combating Bacterial Biofilms: A Focus on Anti-Biofilm Agents and Their Mechanisms of Action. Virulence 9, 522– 554, DOI: 10.1080/21505594.2017.1313372
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Strategies for combating bacterial biofilms: A focus on anti-biofilm agents and their mechanisms of action
Roy, Ranita; Tiwari, Monalisa; Donelli, Gianfranco; Tiwari, Vishvanath
Virulence (2018), 9 (1), 522-554CODEN: VIRUCS; ISSN:2150-5608. (Taylor & Francis, Inc.)
A review. Biofilm refers to the complex, sessile communities of microbes found either attached to a surface or buried firmly in an extracellular matrix as aggregates. The biofilm matrix surrounding bacteria makes them tolerant to harsh conditions and resistant to antibacterial treatments. Moreover, the biofilms are responsible for causing a broad range of chronic diseases and due to the emergence of antibiotic resistance in bacteria it has really become difficult to treat them with efficacy. Furthermore, the antibiotics available till date are ineffective for treating these biofilm related infections due to their higher values of min. inhibitory concn. (MIC) and min. bactericidal concn. (MBC), which may result in in-vivo toxicity. Hence, it is critically important to design or screen anti-biofilm mols. that can effectively minimize and eradicate biofilm related infections. In the present article, we have highlighted the mechanism of biofilm formation with ref. to different models and various methods used for biofilm detection. A major focus has been put on various anti-biofilm mols. discovered or tested till date which may include herbal active compds., chelating agents, peptide antibiotics, lantibiotics and synthetic chem. compds. along with their structures, mechanism of action and their resp. MICs, MBCs, min. biofilm inhibitory concns. (MBICs) as well as the half maximal inhibitory concn. (IC50) values available in the literature so far. Different mode of action of anti biofilm mols. addressed here are inhibition via interference in the quorum sensing pathways, adhesion mechanism, disruption of extracellular DNA, protein, lipopolysaccharides, exopolysaccharides and secondary messengers involved in various signaling pathways. From this study, we conclude that the mols. considered here might be used to treat biofilm-assocd. infections after significant structural modifications, thereby investigating its effective delivery in the host. It should also be ensured that min. effective concn. of these mols. must be capable of eradicating biofilm infections with max. potency without posing any adverse side effects on the host.
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Chen, X., Zhang, L., Zhang, M., Liu, H., Lu, P., and Lin, K. (2018) Quorum Sensing Inhibitors: A Patent Review (2014–2018). Expert Opin. Ther. Pat. 28, 849– 865, DOI: 10.1080/13543776.2018.1541174
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Quorum sensing inhibitors: a patent review (2014-2018)
Chen, Xin; Zhang, Likun; Zhang, Mingxiang; Liu, Huayu; Lu, Panrui; Lin, Kejiang
Expert Opinion on Therapeutic Patents (2018), 28 (12), 849-865CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
A review. Quorum sensing (QS) is a cell d.-dependent phenomenon in which specific pathways are activated after autoinducers (AIs) outside the microorganism reach a threshold concn. QS creates a pos. feedback loop that induces a cascade of gene expression and causes biofilm formation, virulence and sporulation. QS signals are diverse, acyl-homoserine lactone (AHL), AI peptide (AIP) and AI-2 are three major categories of QS signals. QS inhibitors (QSIs) can disrupt or prevent the formation of biofilm and reduce virulence while exerting less selective pressure on the bacteria, suggesting that QSIs are potential alternatives for antibiotics. This review summarized the pertinent patents on QS inhibition available from 2014 to 2018. The authors analyze these patents and provided an overview of them and their potential applications. The main strategy for QS inhibition is to use the analogs of various QS signals to block downstream signal transducers. The inactivation of signal mols. or the stimulation of the immune response is also attractive strategies to inhibit QS. However, addnl. clin. trials are needed to assess their efficacy in mammals. In sum, QS inhibition can reduce the virulence of bacteria without affecting their growth or killing them and the reduced pressure may minimize the increasingly resistance.
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Xiang, H., Cao, F., Ming, D., Zheng, Y., Dong, X., Zhong, X., Mu, D., Li, B., Zhong, L., Cao, J., Wang, L., Ma, H., Wang, T., and Wang, D. (2017) Aloe-Emodin Inhibits Staphylococcus Aureus Biofilms and Extracellular Protein Production at the Initial Adhesion Stage of Biofilm Development. Appl. Microbiol. Biotechnol. 101, 6671– 6681, DOI: 10.1007/s00253-017-8403-5
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Aloe-emodin inhibits Staphylococcus aureus biofilms and extracellular protein production at the initial adhesion stage of biofilm development
Xiang, Hua; Cao, Fengjiao; Ming, Di; Zheng, Yanyang; Dong, Xiaoyun; Zhong, Xiaobo; Mu, Dan; Li, Bangbang; Zhong, Ling; Cao, Junjie; Wang, Lin; Ma, Hongxia; Wang, Tiedong; Wang, Dacheng
Applied Microbiology and Biotechnology (2017), 101 (17), 6671-6681CODEN: AMBIDG; ISSN:0175-7598. (Springer)
Staphylococcus aureus (S. aureus) biofilms are clin. serious and play a crit. role in the persistence of chronic infections due to their ability to resist antibiotics. The inhibition of biofilm formation is viewed as a new strategy for the prevention of S. aureus infections. Here, we demonstrated that min. inhibitory concns. (MICs) of aloe-emodin exhibited no bactericidal activity against S. aureus but affected S. aureus biofilm development in a dose-dependent manner. Further studies indicated that aloe-emodin specifically inhibits the initial adhesion and proliferation stages of S. aureus biofilm development. SEM (SEM) indicated that the S. aureus ATCC29213 biofilm extracellular matrix is mainly composed of protein. Laser scanning confocal microscope assays revealed that aloe-emodin treatment primarily inhibited extracellular protein prodn. Moreover, the Congo red assay showed that aloe-emodin also reduced the accumulation of polysaccharide intercellular adhesin (PIA) on the cell surface. These findings will provide new insights into the mode of action of aloe-emodin in the treatment of infections by S. aureus biofilms.
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Wang, J., Nong, X.-H., Amin, M., and Qi, S.-H. (2018) Hygrocin C from Marine-Derived Streptomyces Sp. SCSGAA 0027 Inhibits Biofilm Formation in Bacillus Amyloliquefaciens SCSGAB0082 Isolated from South China Sea Gorgonian. Appl. Microbiol. Biotechnol. 102, 1417– 1427, DOI: 10.1007/s00253-017-8672-z
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Hygrocin C from marine-derived Streptomyces sp. SCSGAA 0027 inhibits biofilm formation in Bacillus amyloliquefaciens SCSGAB0082 isolated from South China Sea gorgonian
Wang, Jie; Nong, Xu-Hua; Amin, Muhammad; Qi, Shu-Hua
Applied Microbiology and Biotechnology (2018), 102 (3), 1417-1427CODEN: AMBIDG; ISSN:0175-7598. (Springer)
Several ansamycins have been reported to inhibit bacterial biofilm formation and accelerate the eradication of developed biofilms, but little is known about the effect of hygrocin C, an ansamycin, on bacterial biofilm formation. Here, hygrocin C was isolated from the marine-derived Streptomyces sp. SCSGAA 0027 and reported for the first time to be capable of inhibiting the biofilm formation of Staphylococcus aureus and Bacillus amyloliquefaciens SCSGAB0082 with the prodn. of anti-microbial lipopeptides from South China Sea gorgonian Subergorgia suberosa at concns. of less than min. inhibitory concns. Moreover, hygrocin C also promoted the eradication of developed biofilms, affected the biofilm architecture, and lowered the extracellular polymeric matrix formation, cell motility, and surface hydrophobicity in B. amyloliquefaciens, which was in accordance with the inhibition of biofilm formation. Furthermore, transcriptome anal. revealed that hygrocin C altered the transcripts of several genes assocd. with bacterial chemotaxis and flagellar, two-component system and the synthesis of arginine and histidine, which are important for bacterial biofilm formation. In conclusion, hygrocin C could be used as a potential biofilm inhibitor against S. aureus and B. amyloliquefaciens. But further genetic investigations are needed to provide more details for elucidation of the mol. mechanisms responsible for the effects of hygrocin C on B. amyloliquefaciens biofilm formation.
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Wunnoo, S., Saising, J., and Voravuthikunchai, S. P. (2017) Rhodomyrtone Inhibits Lipase Production, Biofilm Formation, and Disorganizes Established Biofilm in Propionibacterium Acnes. Anaerobe 43, 61– 68, DOI: 10.1016/j.anaerobe.2016.12.002
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Rhodomyrtone inhibits lipase production, biofilm formation, and disorganizes established biofilm in Propionibacterium acnes
Wunnoo, Suttiwan; Saising, Jongkon; Voravuthikunchai, Supayang Piyawan
Anaerobe (2017), 43 (), 61-68CODEN: ANAEF8; ISSN:1075-9964. (Elsevier Ltd.)
Virulence enzymes and biofilm a play crucial role in the pathogenesis of Propionibacterium acnes, a major causative agent of acne vulgaris. In the present study, the effects of rhodomyrtone, a pure compd. identified from Rhodomyrtus tomentosa (Aiton) Hassk. leaves ext. against enzyme prodn. and biofilm formation prodn. by 5 clin. isolates and a ref. strain were evaluated. The degree of hydrolysis by both lipase and protease enzymes significantly decreased upon treatment with the compd. at 0.125-0.25 μg/mL (p < 0.05). Lipolytic zones significantly reduced in all isolates while decrease in proteolytic activities was found only in 50% of the isolates. Rhodomyrtone at 1/16MIC and 1/8MIC caused significant redn. in biofilm formation of the clin. isolates (p < 0.05). Percentage viability of P. acnes within mature biofilm upon treated with the compd. at 4MIC and 8MIC ranged between 40% and 85%. Pronounced properties of rhodomyrtone suggest a path towards developing a novel anti-acne agent.
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Falagas, M. E. and Bliziotis, I. A. (2007) Pandrug-Resistant Gram-Negative Bacteria: The Dawn of the Post-Antibiotic Era?. Int. J. Antimicrob. Agents 29, 630– 636, DOI: 10.1016/j.ijantimicag.2006.12.012
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Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era?
Falagas, Matthew E.; Bliziotis, Ioannis A.
International Journal of Antimicrobial Agents (2007), 29 (6), 630-636CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
A review. The evolving problem of antimicrobial resistance in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae has led to the emergence of clin. isolates susceptible to only one class of antimicrobial agents and eventually to pandrug-resistant (PDR) isolates, i.e. resistant to all available antibiotics. The authors reviewed the available evidence from lab. and clin. studies that reported on polymyxin-resistant and/or PDR P. aeruginosa, A. baumannii or K. pneumoniae clin. isolates. Eleven lab. studies reported on isolates with resistance to polymyxins, three of which (including two surveillance studies) also included data regarding PDR isolates. In addn., two clin. studies (from Central and Southern Europe) reported on the clin. characteristics and outcomes of patients infected with PDR isolates. These data suggest that polymyxin-resistant or PDR P. aeruginosa, A. baumannii and K. pneumoniae clin. isolates are currently relatively rare. However, they have important global public health implications because of the therapeutic problems they pose. The fears for the dawn of a post-antibiotic era appear to be justified, at least for these three Gram-neg. bacteria. There must be an increase to preserve the activity of available antibiotics, or at least expand as much as possible the period of their use, while intense research efforts should be focused on the development and introduction into clin. practice of new antimicrobial agents.
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Asker, D., Awad, T. S., Baker, P., Howell, P. L., and Hatton, B. D. (2018) Non-Eluting, Surface-Bound Enzymes Disrupt Surface Attachment of Bacteria by Continuous Biofilm Polysaccharide Degradation. Biomaterials 167, 168– 176, DOI: 10.1016/j.biomaterials.2018.03.016
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Non-eluting, surface-bound enzymes disrupt surface attachment of bacteria by continuous biofilm polysaccharide degradation
Asker, Dalal; Awad, Tarek S.; Baker, Perrin; Howell, P. Lynne; Hatton, Benjamin D.
Biomaterials (2018), 167 (), 168-176CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
Bacterial colonization and biofilm formation on surfaces are typically mediated by the deposition of exopolysaccharides and conditioning protein layers. Pseudomonas aeruginosa is a nosocomial opportunistic pathogen that utilizes strain-specific exopolysaccharides such as Psl, Pel or alginate for both initial surface attachment and biofilm formation. To generate surfaces that resist P. aeruginosa colonization, we covalently bound a Psl-specific glycoside hydrolase (PslGh) to several, chem.-distinct surfaces using amine functionalization (APTMS) and glutaraldehyde (GDA) linking. In situ quartz crystal microbalance (QCM) expts. and fluorescence microscopy demonstrated a complete lack of Psl adsorption on the PslGh-bound surfaces. Covalently-bound PslGh was also found to significantly reduce P. aeruginosa surface attachment and biofilm formation over extended growth periods (8 days). The PslGh surfaces showed a ∼99.9% (∼3-log) redn. in surface assocd. bacteria compared to control (untreated) surfaces, or those treated with inactive enzyme. This work demonstrates a non-eluting 'bioactive' surface that specifically targets a mechanism of cell adhesion, and that surface-bound glycoside hydrolase can significantly reduce surface colonization of bacteria through local, continuous enzymic degrdn. of exopolysaccharide (Psl). These results have significant implications for the surface design of medical devices to keep bacteria in a planktonic state, and therefore susceptible to antibiotics and antimicrobials.
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Pritchard, M. F., Powell, L. C., Jack, A. A., Powell, K., Beck, K., Florance, H., Forton, J., Rye, P. D., Dessen, A., Hill, K. E., and Thomas, D. W. (2017) A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness. Antimicrob. Agents Chemother. 61, 61, DOI: 10.1128/AAC.00762-17
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de la Fuente-Nunez, C., Reffuveille, F., Haney, E. F., Straus, S. K., and Hancock, R. E. W. (2014) Broad-Spectrum Anti-Biofilm Peptide That Targets a Cellular Stress Response. PLoS Pathog. 10, e1004152 DOI: 10.1371/journal.ppat.1004152
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Broad-spectrum anti-biofilm peptide that targets a cellular stress response
de la Fuente-Nunez, Cesar; Reffuveille, Fany; Haney, Evan F.; Straus, Suzana K.; Hancock, Robert E. W.
PLoS Pathogens (2014), 10 (5), e1004152/1-e1004152/12, 12 pp.CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
Bacteria form multicellular communities known as biofilms that cause two thirds of all infections and demonstrate a 10 to 1000 fold increase in adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that specifically target bacterial biofilms. Here we identified a potent anti-biofilm peptide 1018 that worked by blocking (p)ppGpp, an important signal in biofilm development. At concns. that did not affect planktonic growth, peptide treatment completely prevented biofilm formation and led to the eradication of mature biofilms in representative strains of both Gram-neg. and Gram-pos. bacterial pathogens including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Salmonella typhimurium and Burkholderia cenocepacia. Low levels of the peptide led to biofilm dispersal, while higher doses triggered biofilm cell death. We hypothesized that the peptide acted to inhibit a common stress response in target species, and that the stringent response, mediating (p)ppGpp synthesis through the enzymes RelA and SpoT, was targeted. Consistent with this, increasing (p)ppGpp synthesis by addn. of serine hydroxamate or over-expression of relA led to reduced susceptibility to the peptide. Furthermore, relA and spoT mutations blocking prodn. of (p)ppGpp replicated the effects of the peptide, leading to a redn. of biofilm formation in the four tested target species. Also, eliminating (p)ppGpp expression after two days of biofilm growth by removal of arabinose from a strain expressing relA behind an arabinose-inducible promoter, reciprocated the effect of peptide added at the same time, leading to loss of biofilm. NMR and chromatog. studies showed that the peptide acted on cells to cause degrdn. of (p)ppGpp within 30 min, and in vitro directly interacted with ppGpp. We thus propose that 1018 targets (p)ppGpp and marks it for degrdn. in cells. Targeting (p)ppGpp represents a new approach against biofilm-related drug resistance.
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Pletzer, D., Wolfmeier, H., Bains, M., and Hancock, R. E. W. (2017) Synthetic Peptides to Target Stringent Response-Controlled Virulence in a Pseudomonas Aeruginosa Murine Cutaneous Infection Model. Front. Microbiol. 8, 1867, DOI: 10.3389/fmicb.2017.01867
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Synthetic Peptides to Target Stringent Response-Controlled Virulence in a Pseudomonas aeruginosa Murine Cutaneous Infection Model
Pletzer Daniel; Wolfmeier Heidi; Bains Manjeet; Hancock Robert E W
Frontiers in microbiology (2017), 8 (), 1867 ISSN:1664-302X.
Microorganisms continuously monitor their surroundings and adaptively respond to environmental cues. One way to cope with various stress-related situations is through the activation of the stringent stress response pathway. In Pseudomonas aeruginosa this pathway is controlled and coordinated by the activity of the RelA and SpoT enzymes that metabolize the small nucleotide secondary messenger molecule (p)ppGpp. Intracellular ppGpp concentrations are crucial in mediating adaptive responses and virulence. Targeting this cellular stress response has recently been the focus of an alternative approach to fight antibiotic resistant bacteria. Here, we examined the role of the stringent response in the virulence of P. aeruginosa PAO1 and the Liverpool epidemic strain LESB58. A ΔrelA/ΔspoT double mutant showed decreased cytotoxicity toward human epithelial cells, exhibited reduced hemolytic activity, and caused down-regulation of the expression of the alkaline protease aprA gene in stringent response mutants grown on blood agar plates. Promoter fusions of relA or spoT to a bioluminescence reporter gene revealed that both genes were expressed during the formation of cutaneous abscesses in mice. Intriguingly, virulence was attenuated in vivo by the ΔrelA/ΔspoT double mutant, but not the relA mutant nor the ΔrelA/ΔspoT complemented with either gene. Treatment of a cutaneous P. aeruginosa PAO1 infection with anti-biofilm peptides increased animal welfare, decreased dermonecrotic lesion sizes, and reduced bacterial numbers recovered from abscesses, resembling the phenotype of the ΔrelA/ΔspoT infection. It was previously demonstrated by our lab that ppGpp could be targeted by synthetic peptides; here we demonstrated that spoT promoter activity was suppressed during cutaneous abscess formation by treatment with peptides DJK-5 and 1018, and that a peptide-treated relA complemented stringent response double mutant strain exhibited reduced peptide susceptibility. Overall these data strongly indicated that synthetic peptides target the P. aeruginosa stringent response in vivo and thus offer a promising novel therapeutic approach.
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Christensen, L. D., van Gennip, M., Jakobsen, T. H., Alhede, M., Hougen, H. P., Hoiby, N., Bjarnsholt, T., and Givskov, M. (2012) Synergistic Antibacterial Efficacy of Early Combination Treatment with Tobramycin and Quorum-Sensing Inhibitors against Pseudomonas Aeruginosa in an Intraperitoneal Foreign-Body Infection Mouse Model. J. Antimicrob. Chemother. 67, 1198– 1206, DOI: 10.1093/jac/dks002
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Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model
Christensen, Louise D.; van Gennip, Maria; Jakobsen, Tim H.; Alhede, Morten; Hougen, Hans Petter; Hoiby, Niels; Bjarnsholt, Thomas; Givskov, Michael
Journal of Antimicrobial Chemotherapy (2012), 67 (5), 1198-1206CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
Quorum sensing (QS)-deficient Pseudomonas aeruginosa biofilms formed in vitro are more susceptible to tobramycin than QS-proficient P. aeruginosa biofilms, and combination treatment with a QS inhibitor (QSI) and tobramycin shows synergistic effects on the killing of in vitro biofilms. We extended these results to an in vivo P. aeruginosa foreign-body biofilm model. The effect of treatment initiated prophylactically was compared with treatment initiated 11 days post-insertion. Silicone tube implants pre-colonized with wild-type P. aeruginosa were inserted into the peritoneal cavity of BALB/c mice. Mice were treated with i.p. or s.c. injections of the QSIs furanone C-30, ajoene or horseradish juice ext. in combination with tobramycin. Mice were euthanized on day 1, 2, 3 or 14 post-infection for the estn. of quant. bacteriol., histopathol. and cytokine measurements. Combination treatment of P. aeruginosa resulted in a significantly lower cfu per implant as compared with the placebo groups for all QSIs tested. For early-initiated treatment, a significant difference in clearing was also obsd. between the combination group and the single-treatment groups, and between the placebo group and the single-treatment groups. In one case a significant difference in clearing was found between the two single-treatment groups. Synergistic antimicrobial efficacy could be achieved when treating mice with both a QSI and tobramycin, resulting in an increased clearance of P. aeruginosa in a foreign-body infection model. Our study highlights the important prospects in developing an early combinatory treatment strategy for chronic infections.
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Kissoyan, K. A. B., Bazzi, W., Hadi, U., and Matar, G. M. (2016) The Inhibition of Pseudomonas Aeruginosa Biofilm Formation by Micafungin and the Enhancement of Antimicrobial Agent Effectiveness in BALB/c Mice. Biofouling 32, 779– 786, DOI: 10.1080/08927014.2016.1199021
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The inhibition of Pseudomonas aeruginosa biofilm formation by micafungin and the enhancement of antimicrobial agent effectiveness in BALB/c mice
Kissoyan, Kohar Annie B.; Bazzi, Wael; Hadi, Usamah; Matar, Ghassan M.
Biofouling (2016), 32 (7), 779-786CODEN: BFOUEC; ISSN:0892-7014. (Taylor & Francis Ltd.)
Micafungin inhibits biofilm formation by impeding 1,3-β-D-glucan synthesis in Candida albicans. Since Pseudomonas aeruginosa also has 1,3-β-D-glucan in its cell wall, this study assessed the effects of antibacterial agents in vitro and in vivo on micafungin-treated biofilm-forming P. aeruginosa isolates. After treatment with micafungin as well as with a panel of four antibacterial agents, biofilm prodn. was significantly reduced as measured by spectrophotometry. The relative mRNA transcription levels for the genes encoding pellicles (pelC) and cell wall 1,3-β-D-glucan (ndvB), which were measured by quant. reverse transcription PCR (qRT-PCR), significantly decreased with micafungin treatment. In vivo, the survival rates of P. aeruginosa-infected BALB/c mice significantly increased after combined treatment with micafungin and each of the antibacterial agents. Of these treatments, the combination of micafungin with levofloxacin had the highest survival rate; this combination was the most effective treatment against P. aeruginosa-induced infection.
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Maiden, M. M., Hunt, A. M. A., Zachos, M. P., Gibson, J. A., Hurwitz, M. E., Mulks, M. H., and Waters, C. M. (2018) Triclosan Is an Aminoglycoside Adjuvant for Eradication of Pseudomonas Aeruginosa Biofilms. Antimicrob. Agents Chemother. 62, e00146-18 DOI: 10.1128/AAC.00146-18
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266
Worthington, R. J. and Melander, C. (2013) Combination Approaches to Combat Multidrug-Resistant Bacteria. Trends Biotechnol. 31, 177– 184, DOI: 10.1016/j.tibtech.2012.12.006
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Combination approaches to combat multidrug-resistant bacteria
Worthington, Roberta J.; Melander, Christian
Trends in Biotechnology (2013), 31 (3), 177-184CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
A review. The increasing prevalence of infections caused by multidrug-resistant bacteria is a global health problem that has been exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein, we describe recent developments toward combination therapies for the treatment of multidrug-resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems (TCSs). We also discuss screening of libraries of previously approved drugs to identify nonobvious antimicrobial adjuvants.
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Tyers, M. and Wright, G. D. (2019) Drug Combinations: A Strategy to Extend the Life of Antibiotics in the 21st Century. Nat. Rev. Microbiol. 17, 141– 155, DOI: 10.1038/s41579-018-0141-x
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Drug combinations: a strategy to extend the life of antibiotics in the 21st century
Tyers, Mike; Wright, Gerard D.
Nature Reviews Microbiology (2019), 17 (3), 141-155CODEN: NRMACK; ISSN:1740-1526. (Nature Research)
Antimicrobial resistance threatens a resurgence of life-threatening bacterial infections and the potential demise of many aspects of modern medicine. Despite intensive drug discovery efforts, no new classes of antibiotics have been developed into new medicines for decades, in large part owing to the stringent chem., biol. and pharmacol. requisites for effective antibiotic drugs. Combinations of antibiotics and of antibiotics with non-antibiotic activity-enhancing compds. offer a productive strategy to address the widespread emergence of antibiotic-resistant strains. In this Review, we outline a theor. and practical framework for the development of effective antibiotic combinations.
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Schmid, A., Wolfensberger, A., Nemeth, J., Schreiber, P. W., Sax, H., and Kuster, S. P. (2019) Monotherapy versus Combination Therapy for Multidrug-Resistant Gram-Negative Infections: Systematic Review and Meta-Analysis. Sci. Rep. 9, 15290, DOI: 10.1038/s41598-019-51711-x
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Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis
Schmid Adrian; Wolfensberger Aline; Nemeth Johannes; Schreiber Peter W; Sax Hugo; Kuster Stefan P
Scientific reports (2019), 9 (1), 15290 ISSN:.
Infections caused by carbapenemase-producing, multidrug-resistant (MDR), or extensively drug-resistant (XDR) Gram-negative bacteria constitute a major therapeutic challenge. Whether combination antibiotic therapy is superior to monotherapy remains unknown. In this systematic review and meta-analysis OVID MEDLINE, EMBASE, PubMed, The Cochrane Library, and Scopus databases were searched for randomized controlled trials (RCTs) and observational studies published by December 2016 comparing mono- with combination antibiotic therapy for infections with carbapenemase-producing, MDR, or XDR Gram-negative bacteria. Mortality and clinical cure rates served as primary and secondary outcome measures, respectively. Of 8847 initially identified studies, 53 studies - covering pneumonia (n = 10 studies), blood stream (n = 15), osteoarticular (n = 1), and mixed infections (n = 27) - were included. 41% (n = 1848) of patients underwent monotherapy, and 59% (n = 2666) combination therapy. In case series/cohort studies (n = 45) mortality was lower with combination- vs. monotherapy (RR 0.83, CI 0.73-0.93, p = 0.002, I(2) = 24%). Subgroup analysis revealed lower mortality with combination therapy with at least two in-vitro active antibiotics, in blood stream infections, and carbapenemase-producing Enterobacteriaceae. No mortality difference was seen in case-control studies (n = 6) and RCTs (n = 2). Cure rates did not differ regardless of study type. The two included RCTs had a high and unknown risk of bias, respectively. 16.7% (1/6) of case-control studies and 37.8% (17/45) of cases series/cohort studies were of good quality, whereas quality was poor in the remaining studies. In conclusion, combination antimicrobial therapy of multidrug-resistant Gram-negative bacteria appears to be superior to monotherapy with regard to mortality.
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Drusano, G. L., Hope, W., MacGowan, A., and Louie, A. (2016) Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1. Antimicrob. Agents Chemother. 60, 1194– 1201, DOI: 10.1128/AAC.02231-15
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Suppression of emergence of resistance in pathogenic bacteria: keeping our powder dry, part 2
Drusano, G. L.; Hope, William; MacGowan, Alasdair; Louie, Arnold
Antimicrobial Agents and Chemotherapy (2016), 60 (3), 1194-1201CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done. The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence. A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clin. breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like Pseudomonas aeruginosa, Acinetobacter spp., and multidrug-resistant (MDR) Enterobacteriaceae. These lessons need to be applied to our old drugs as well to preserve them and to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chem. entities should have a resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects.
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Lee, J., Patel, G., Huprikar, S., Calfee, D. P., and Jenkins, S. G. (2009) Decreased Susceptibility to Polymyxin B during Treatment for Carbapenem-Resistant Klebsiella Pneumoniae Infection. J. Clin. Microbiol. 47, 1611– 2, DOI: 10.1128/JCM.02466-08
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Decreased susceptibility to polymyxin B during treatment for carbapenem-resistant Klebsiella pneumoniae infection
Lee Jooyun; Patel Gopi; Huprikar Shirish; Calfee David P; Jenkins Stephen G
Journal of clinical microbiology (2009), 47 (5), 1611-2 ISSN:.
There is no expanded citation for this reference.
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Goss, C. H. and Muhlebach, M. S. (2011) Review: Staphylococcus Aureus and MRSA in Cystic Fibrosis. J. Cystic Fibrosis 10, 298– 306, DOI: 10.1016/j.jcf.2011.06.002
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Review: Staphylococcus aureus and MRSA in cystic fibrosis
Goss, Christopher H.; Muhlebach, Marianne S.
Journal of Cystic Fibrosis (2011), 10 (5), 298-306CODEN: JCFOAC; ISSN:1569-1993. (Elsevier B.V.)
A review. Background: Staphylococcus aureus (S. aureus) is one of the earliest bacteria detected in infants and children with cystic fibrosis (CF). The rise of methicillin resistant S. aureus (MRSA) in the last 10 years has caused a lot of attention to this organism. Results: The aim of this review is to provide a general overview of methicillin sensitive S. aureus (MSSA) and MRSA, discuss special aspects of S. aureus in cystic fibrosis, and to review treatment concepts. Microbiol. of the organism will be reviewed along with data regarding the epidemiol. of both MSSA and MRSA. Antibiotic treatments both in regards to acute management and eradication of MSSA and MRSA will be reviewed. Prophylaxis of MSSA in CF remains controversial. Treatment with anti-staphylococcal agents reduces the infection rate with MSSA but may lead to a higher rate of infection with P. aeruginosa. In regards to MRSA, there is a paucity of clin. data regarding approaches to eradication. Conclusions: To advance the care of CF patients, controlled clin. trials are urgently needed to find the optimal approach to treating CF patients who are infected with either MSSA or MRSA.
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McCaughey, G., Diamond, P., Elborn, J. S., McKevitt, M., and Tunney, M. M. (2013) Resistance Development of Cystic Fibrosis Respiratory Pathogens When Exposed to Fosfomycin and Tobramycin Alone and in Combination under Aerobic and Anaerobic Conditions. PLoS One 8, e69763 DOI: 10.1371/journal.pone.0069763
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Resistance development of cystic fibrosis respiratory pathogens when exposed to fosfomycin and tobramycin alone and in combination under aerobic and anaerobic conditions
McCaughey, Gerard; Diamond, Paul; Elborn, J. Stuart; McKevitt, Matt; Tunney, Michael M.
PLoS One (2013), 8 (7), e69763CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
Although antibiotics from different classes are frequently prescribed in combination to prevent the development of resistance amongst Cystic Fibrosis (CF) respiratory pathogens, there is a lack of data as to the efficacy of this approach. The authors have previously shown that a 4:1 (wt./wt.) combination of fosfomycin and tobramycin (F:T) has excellent activity against CF pathogens with increased activity under physiol. relevant anaerobic conditions. Therefore, the aim of this study was to det. whether F:T could delay or prevent the onset of resistance compared to either fosfomycin or tobramycin alone under aerobic and anaerobic conditions. The frequency of spontaneous mutants arising following exposure to fosfomycin, tobramycin and F:T was detd. for clin. Pseudomonas aeruginosa and MRSA isolates under aerobic and anaerobic conditions. The effect of sub-inhibitory concns. of fosfomycin, tobramycin and F:T on the induction of resistance was also investigated, with the stability of resistance and fitness cost assocd. with resistance assessed if it developed. P. aeruginosa and MRSA isolates had a lower frequency of spontaneous mutants to F:T compared to fosfomycin and tobramycin under both aerobic and anaerobic conditions. There was a max. two-fold increase in F:T MICs when P. aeruginosa and MRSA isolates were passaged in sub-inhibitory F:T for 12 days. In contrast, sequential resistance to fosfomycin and tobramycin developed quickly (n = 3 days for both) after passage in sub-inhibitory concns. Once developed, both fosfomycin and tobramycin resistance was stable and not assocd. with a biol. fitness cost to either P. aeruginosa or MRSA isolates. The results of this study suggest that F:T may prevent the development of resistance compared to fosfomycin or tobramycin alone under aerobic and physiol. relevant anaerobic conditions. F:T may be a potential treatment option in CF patients chronically colonized by MRSA and/or P. aeruginosa.
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Monedero, I. and Caminero, J. A. (2010) Management of Multidrug-Resistant Tuberculosis: An Update. Ther. Adv. Respir. Dis. 4, 117– 127, DOI: 10.1177/1753465810365884
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Management of multidrug-resistant tuberculosis: an update
Monedero Ignacio; Caminero Jose A
Therapeutic advances in respiratory disease (2010), 4 (2), 117-27 ISSN:.
Multidrug-resistant tuberculosis (MDR-TB) is threatening control of TB in many parts of the world. As a result of limited treatment options, patients have a poor prognosis and low chances of cure. This situation can be exacerbated by HIV epidemics. In some cases, the risk exists of a real shift from susceptible to resistant strains. Despite its relevance, currently there are more contradictions and confusion surrounding MDR-TB than hard evidence. No randomized controlled trials have been performed and published evidence is limited. Rather than just the selection of expensive drugs, MDR-TB management requires well-structured programmes with a comprehensive approach, which involve the actions of a wide range of participants. Even with current investments in research and development, new drugs and vaccines will take many years to be applied in low and middle income countries. The most successful results will depend on the optimization of existing tools. The majority of the patients, even those with extensive patterns of bacilli resistance, have a possibility of cure if current clinical knowledge and effective logistics are applied. This paper is a critical review of current best practice regarding the diagnosis and treatment of MDR-TB.
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REX Consortium (2013) Heterogeneity of Selection and the Evolution of Resistance. Trends Ecol. Evol. 28, 110– 118, DOI: 10.1016/j.tree.2012.09.001
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Takesue, Y., Nakajima, K., Ichiki, K., Ishihara, M., Wada, Y., Takahashi, Y., Tsuchida, T., and Ikeuchi, H. (2010) Impact of a Hospital-Wide Programme of Heterogeneous Antibiotic Use on the Development of Antibiotic-Resistant Gram-Negative Bacteria. J. Hosp. Infect. 75, 28– 32, DOI: 10.1016/j.jhin.2009.11.022
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Impact of a hospital-wide programme of heterogeneous antibiotic use on the development of antibiotic-resistant Gram-negative bacteria
Takesue Y; Nakajima K; Ichiki K; Ishihara M; Wada Y; Takahashi Y; Tsuchida T; Ikeuchi H
The Journal of hospital infection (2010), 75 (1), 28-32 ISSN:.
Although antibiotic heterogeneity has been proposed as a strategy to limit the emergence of antibiotic resistance, few clinical studies have been conducted to validate the concept. This paper evaluates a hospital-wide strategy of heterogeneous antibiotic use intended to reduce infections caused by resistant Gram-negative rods (GNR). A strategy termed 'periodic antimicrobial monitoring and supervision' (PAMS) was implemented between September 2006 and February 2008. The 18 month intervention period was compared with the preceding 18 months (12 months pre-establishment and 6 months preparation). During PAMS, recommended, restricted and off-supervised classes of antibiotics active against more resistant GNR were changed every 3 months according to the antimicrobial usage density and rates of resistance to those antibiotics in Pseudomonas aeruginosa during the preceding term. Usage of five categories of antibiotics was supervised by four full-time staff. Antibiotic heterogeneity was estimated using the Peterson index (AHI). AHI estimates were 0.66 and 0.74 during the observation period but rose after the introduction of PAMS (period 1: 0.84; period 2: 0.94; period 3: 0.88). The incidence of patients from whom resistant GNR were isolated decreased significantly (P<0.001), whereas isolation of multidrug-resistant (MDR) GNR decreased from 1.7% to 0.5% (P<0.001). There was no significant difference in the incidence of extended spectrum beta-lactamase-producing organisms. Rates of imipenem resistance among Pseudomonas aeruginosa improved during PAMS2. PAMS facilitated hospital-wide heterogeneous antibiotic usage which was associated with reduced rates of resistant GNR.
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Raymond, B. (2019) Five Rules for Resistance Management in the Antibiotic Apocalypse, a Road Map for Integrated Microbial Management. Evol. Appl. 12, 1079– 1091, DOI: 10.1111/eva.12808
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Five rules for resistance management in the antibiotic apocalypse, a road map for integrated microbial management
Raymond Ben
Evolutionary applications (2019), 12 (6), 1079-1091 ISSN:1752-4571.
Resistance to new antimicrobials can become widespread within 2-3 years. Resistance problems are particularly acute for bacteria that can experience selection as both harmless commensals and pathogenic hospital-acquired infections. New drugs, although welcome, cannot tackle the antimicrobial resistance crisis alone: new drugs must be partnered with more sustainable patterns of use. However, the broader experience of resistance management in other disciplines, and the assumptions on which resistance rests, is not widely appreciated in clinical and microbiological disciplines. Improved awareness of the field of resistance management could improve clinical outcomes and help shape novel solutions. Here, the aim is to develop a pragmatic approach to developing a sustainable integrated means of using antimicrobials, based on an interdisciplinary synthesis of best practice, recent theory and recent clinical data. This synthesis emphasizes the importance of pre-emptive action and the value of reducing the supply of genetic novelty to bacteria under selection. The weight of resistance management experience also cautions against strategies that over-rely on the fitness costs of resistance or low doses. The potential (and pitfalls) of shorter courses, antibiotic combinations and antibiotic mixing or cycling are discussed in depth. Importantly, some of variability in the success of clinical trials of mixing approaches can be explained by the number and diversity of drugs in a trial, as well as whether trials encompass single wards or the wider transmission network that is a hospital. Consideration of the importance of data, and of the initially low frequency of resistance, leads to a number of additional recommendations. Overall, reduction in selection pressure, interference with the transmission of problematic genotypes and multidrug approaches (combinations, mixing or cycling) are all likely to be required for sustainability and the protection of forthcoming drugs.
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Paul, M., Lador, A., Grozinsky-Glasberg, S., and Leibovici, L. (2014) Beta Lactam Antibiotic Monotherapy versus Beta Lactam-Aminoglycoside Antibiotic Combination Therapy for Sepsis. Cochrane database Syst. Rev. (1), CD003344, DOI: 10.1002/14651858.CD003344.pub3
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Tamma, P. D., Cosgrove, S. E., and Maragakis, L. L. (2012) Combination Therapy for Treatment of Infections with Gram-Negative Bacteria. Clin. Microbiol. Rev. 25, 450– 470, DOI: 10.1128/CMR.05041-11
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278
Combination therapy for treatment of infections with Gram-negative bacteria
Tamma, Pranita D.; Cosgrove, Sara E.; Maragakis, Lisa L.
Clinical Microbiology Reviews (2012), 25 (3), 450-470CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
The findings for this review as well as from several meta-analyses do not support the use of combination antimicrobial therapy for definitive treatment of infections with Gram-neg. bacteria. It should be noted that combination therapy may have some value in a specific subset of patients with severe sepsis, and well-controlled randomized studies are necessary to answer this question. Many of the early studies that supported the concept of combination therapy used aminoglycoside monotherapy as the comparator group, a clin. strategy that has been subsequently shown to be inferior. With the advent of broad-spectrum antipseudomonal β-lactam agents, studies have not shown an advantage to adding a second agent. There are three potential advantages to combination antimicrobial therapy for infections with Gram-neg. bacteria that are generally cited: (i) an increased likelihood that the infective pathogen will be susceptible to at least one of the components of an empiric combination regimen, (ii) the synergistic effect afforded by the use of two agents, and (iii) protection against emergence of resistance with combination therapy. With regard to the first point, the use of empiric combination therapy for critically ill patients is certainly appropriate to broaden the spectrum of activity and to increase the likelihood that the regimen contains a single agent that is active against the pathogen, but there is insufficient evidence showing a benefit of a second agent for continued therapy once pathogens and antimicrobial susceptibilities are known. Although synergy may have a role when treating a highly resistant organism with MICs in the intermediate to resistant range, assuming that the pathogen is susceptible to one antibiotic, there does not appear to be a "synergistic" benefit that translates to an incremental clin. benefit with the addn. of a second agent. Finally, clin. studies of infections with Gram-neg. bacteria have shown no difference in the emergence of resistance during antimicrobial therapy with combination therapy vs. monotherapy. Ensuring that the dose, frequency of administration, and duration over which an antibiotic is infused are optimized is likely more important in the prevention of resistance than the addn. of a second agent. As the flow of new antibacterial drugs into the market has slowed coupled with the increasing prevalence of MDRGN infections, saving the second agent for when actually necessary is vital in the war against antimicrobial resistance.
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The authors present and analyze a series of math. models for the emergence of resistance during antibiotic treatment of an infected host. The models consider the population dynamics of antibiotic-sensitive and -resistant bacteria during the course of treatment and addresses the following problems: (i) the probability of obtaining a resistant mutant during the course of treatment as a function of antibiotic exposure; (ii) the conditions under which high, infrequent doses of an antibiotic are predicted to succeed in preventing the emergence of resistance; (iii) the conditions for the success of multiple drug treatment in suppressing the emergency of resistance and the relation between antibiotic synergism and suppression of resistance; and (i.v.) the conditions under which non-adherence to the prescribed treatment regimen is predicted to result in treatment failure due to resistance. The authors analyze the predictions of the model for interpreting and extrapolating existing exptl. studies of treatment efficacy and for optimizing treatment protocols to prevent the emergence of resistance.
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When the most potent combination of antibiotics selects for the greatest bacterial load: the smile-frown transition
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PLoS Biology (2013), 11 (4), e1001540CODEN: PBLIBG; ISSN:1545-7885. (Public Library of Science)
Conventional wisdom holds that the best way to treat infection with antibiotics is to 'hit early and hit hard'. A favored strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal. We combine math. modeling, evolution expts., whole genome sequencing and genetic manipulation of a resistance mechanism to demonstrate that deploying synergistic antibiotics can, in practice, be the worst strategy if bacterial clearance is not achieved after the first treatment phase. As treatment proceeds, it is only to be expected that the strength of antibiotic synergy will diminish as the frequency of drug-resistant bacteria increases. Indeed, antibiotic efficacy decays exponentially in our five-day evolution expts. However, as the theory of competitive release predicts, drug-resistant bacteria replicate fastest when their drug-susceptible competitors are eliminated by overly-aggressive treatment. Here, synergy exerts such strong selection for resistance that an antagonism consistently emerges by day 1 and the initially most aggressive treatment produces the greatest bacterial load, a fortiori greater than if just one drug were given. Whole genome sequencing reveals that such rapid evolution is the result of the amplification of a genomic region contg. four drug-resistance mechanisms, including the acrAB efflux operon. When this operon is deleted in genetically manipulated mutants and the evolution expt. repeated, antagonism fails to emerge in five days and antibiotic synergy is maintained for longer. We therefore conclude that unless super-inhibitory doses are achieved and maintained until the pathogen is successfully cleared, synergistic antibiotics can have the opposite effect to that intended by helping to increase pathogen load where, and when, the drugs are found at sub-inhibitory concns.
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A review. The authors discuss the evolutionary dynamics of antibiotic resistance in bacteria in relation to the complex interplay between population genetic factors and the spatial and temporal pattern of antibiotic use. Despite efforts from a range of disciplines, our ability to predict and combat the evolution of antibiotic resistance in pathogenic bacteria is limited. This is because resistance evolution involves a complex interplay between the specific drug, bacterial genetics and both natural and treatment ecol. Incorporating details of the mol. mechanisms of drug resistance and ecol. into evolutionary models has proved useful in predicting the dynamics of resistance evolution. However, putting these models to practical use will require extensive collaboration between mathematicians, mol. biologists, evolutionary ecologists and clinicians.
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Hegreness, M., Shoresh, N., Damian, D., Hartl, D., and Kishony, R. (2008) Accelerated Evolution of Resistance in Multidrug Environments. Proc. Natl. Acad. Sci. U. S. A. 105, 13977– 13981, DOI: 10.1073/pnas.0805965105
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Accelerated evolution of resistance in multidrug environments
Hegreness, Matthew; Shoresh, Noam; Damian, Doris; Hartl, Daniel; Kishony, Roy
Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (37), 13977-13981CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The emergence of resistance during multidrug chemotherapy impedes the treatment of many human diseases, including malaria, TB, HIV, and cancer. Although certain combination therapies have long been known to be more effective in curing patients than single drugs, the impact of such treatments on the evolution of drug resistance is unclear. In particular, very little is known about how the evolution of resistance is affected by the nature of the interactions-synergy or antagonism-between drugs. Here we directly measure the effect of various inhibitory and subinhibitory drug combinations on the rate of adaptation. We develop an automated assay for monitoring the parallel evolution of hundreds of Escherichia coli populations in a two-dimensional grid of drug gradients over many generations. We find a correlation between synergy and the rate of adaptation, whereby evolution in more synergistic drug combinations, typically preferred in clin. settings, is faster than evolution in antagonistic combinations. We also find that resistance to some synergistic combinations evolves faster than resistance to individual drugs. The accelerated evolution may be due to a larger selective advantage for resistance mutations in synergistic treatments. We describe a simple geometric model in which mutations conferring resistance to one drug of a synergistic pair prevent not only the inhibitory effect of that drug but also its enhancing effect on the other drug. Future study of the profound impact that synergy and other drug-pair properties can have on the rate of adaptation may suggest new treatment strategies for combating the spread of antibiotic resistance.
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Liu, J., Gefen, O., Ronin, I., Bar-Meir, M., and Balaban, N. Q. (2020) Effect of Tolerance on the Evolution of Antibiotic Resistance under Drug Combinations. Science 367, 200– 204, DOI: 10.1126/science.aay3041
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Effect of tolerance on the evolution of antibiotic resistance under drug combinations
Liu, Jiafeng; Gefen, Orit; Ronin, Irine; Bar-Meir, Maskit; Balaban, Nathalie Q.
Science (Washington, DC, United States) (2020), 367 (6474), 200-204CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
Drug combinations are widely used in clin. practice to prevent the evolution of resistance. However, little is known about the effect of tolerance, a different mode of survival, on the efficacy of drug combinations for preventing the evolution of resistance. In this work, we monitored Staphylococcus aureus strains evolving in patients under treatment. We detected the rapid emergence of tolerance mutations, followed by the emergence of resistance, despite the combination treatment. Evolution expts. on the clin. strains in vitro revealed a new way by which tolerance promotes the evolution of resistance under combination treatments. Further expts. under different antibiotic classes reveal the generality of the effect. We conclude that tolerance is an important factor to consider in designing combination treatments that prevent the evolution of resistance.
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Cite this: ACS Infect. Dis. 2020, 6, 6, 1346–1365

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Published March 10, 2020

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Abstract
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Figure 1
Figure 1. Examples for multiple mechanisms of action of antibiotics. (A–C) Antibiotics with intrinsically multi-effective properties. (A) Disrupting cytoplasmic membrane integrity, e.g., by gramicidin S, affects membrane-bound processes, most prominently respiration and lipid II synthesis. (B) Binding of antibiotics to lipid II or its carrier molecule undecaprenyl(pyro)phosphate (here: bacitracin binding UDP-PP) depletes the carrier pool, affecting both the synthesis of wall teichoic acids (WTA) and lipid II. (C) Inhibition of ATP synthase, e.g., by bedaquiline, leads to the depletion of the cellular ATP pool and thus inhibition of multiple metabolic processes. (D–F) Antibiotics with multiple targets. (D) β-Lactams (here imipenem) typically inhibit more than one penicillin-binding protein (PBP). (E) Polymyxins like polymyxin B or colistin disrupt both the outer and inner membrane of Gram-negative bacteria. (F) Type A lantibiotics like nisin bind to lipid II and use it as a docking molecule to form a transmembrane pore.
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Figure 2
Figure 2. Prevention of resistance development by combination therapy. Sulfonamide antibiotics are typically given together with trimethoprim to prevent fast target mutation of a single enzyme.
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Figure 3
Figure 3. Mechanisms of synergy. (A) Targeting the same molecule (here, plectasin in red–yellow and dalbavancin in green–blue), (B) targeting the same pathway (here, plectasin in red–yellow and moenomycin in green–blue), (C) targeting a related process (here, LL-37 in green–blue and teicoplanin in red–yellow), and (D) improving target accessibility (here, colistin in red–yellow and minocycline in green–blue).
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Figure 4
Figure 4. Mechanisms of resistance-breaking and antibiotic-potentiating compounds. (A) Cell envelope permeabilizers, (B) antibiotic sensitizers, (C) β-lactamase inhibitors, (D) inhibitors of aminoglycoside-modifying enzymes, (E) efflux pump inhibitors, and (F) biofilm inhibitors. red–yellow: antibiotic; magenta–turquoise: potentiator.
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  Scheffers, Dirk-Jan; Pinho, Mariana G.
  Microbiology and Molecular Biology Reviews (2005), 69 (4), 585-607CODEN: MMBRF7; ISSN:1092-2172. (American Society for Microbiology)
  A review. In order to maintain shape and withstand intracellular pressure, most bacteria are surrounded by a cell wall that consists mainly of the cross-linked polymer peptidoglycan (PG). The importance of PG for the maintenance of bacterial cell shape is underscored by the fact that, for various bacteria, several mutations affecting PG synthesis are assocd. with cell shape defects. In recent years, the application of fluorescence microscopy to the field of PG synthesis has led to an enormous increase in data on the relationship between cell wall synthesis and bacterial cell shape. First, a novel staining method enabled the visualization of PG precursor incorporation in live cells. Second, penicillin-binding proteins (PBPs), which mediate the final stages of PG synthesis, have been localized in various model organisms by means of immunofluorescence microscopy or green fluorescent protein fusions. In this review, we integrate the knowledge on the last stages of PG synthesis obtained in previous studies with the new data available on localization of PG synthesis and PBPs, in both rod-shaped and coccoid cells. We discuss a model in which, at least for a subset of PBPs, the presence of substrate is a major factor in detg. PBP localization.
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9. 9
  Drlica, K., Malik, M., Kerns, R. J., and Zhao, X. (2008) Quinolone-Mediated Bacterial Death. Antimicrob. Agents Chemother. 52, 385– 392, DOI: 10.1128/AAC.01617-06
  9
  Quinolone-mediated bacterial death
  Drlica, Karl; Malik, Muhammad; Kerns, Robert J.; Zhao, Xilin
  Antimicrobial Agents and Chemotherapy (2008), 52 (2), 385-392CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  A review. In the present review we consider cell death through a two-part "poison" hypothesis in which quinolones form reversible drug-topoisomerase-DNA complexes that subsequently lead to several types of irreversible (lethal) damage. Topics discussed include: quinolone-topoisomerase-DNA complexes; inhibition of DNA replication; SOS response and cell filamentation; toxin-antitoxin modules and programmed cell death; chromosome fragmentation; and destabilization of cleaved complexes.
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10. 10
  Chopra, I. (2007) Bacterial RNA Polymerase: A Promising Target for the Discovery of New Antimicrobial Agents. Curr. Opin. Investig. Drugs 8, 600– 607
  10
  Bacterial RNA polymerase: a promising target for the discovery of new antimicrobial agents
  Chopra, Ian
  Current Opinion in Investigational Drugs (Thomson Scientific) (2007), 8 (8), 600-607CODEN: COIDAZ; ISSN:1472-4472. (Thomson Scientific)
  A review. Prokaryotic DNA-dependent RNA polymerase (RNAP) is a multi-subunit enzyme responsible for transcription in bacteria. It is an important target for antibacterial chemotherapy because it is essential for bacterial growth and survival, and possesses features that distinguish it from mammalian counterparts. The rifamycins are currently the only class of RNAP inhibitors that have been approved for clin. use, and consequently bacterial RNAP remains relatively underexploited as an antibacterial drug target. However, improved understanding of the mol. basis of rifamycin action, revealed by X-ray crystallog. studies, has resulted in the development of new rifamycins, such as the benzoxazinorifamycins, with improved properties. Structural studies on other RNAP inhibitors have also been described, and a no. of older inhibitors now await detailed investigation to provide mol. explanations for their modes of action. New approaches have also resulted in the discovery of inhibitors of RNAP assembly. This review discusses various RNAP inhibitors in the context of their modes of action and potential development for therapeutic application. Opportunities for the discovery of new inhibitors are also discussed.
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11. 11
  Sköld, O. (2000) Sulfonamide Resistance: Mechanisms and Trends. Drug Resist. Updates 3, 155– 160, DOI: 10.1054/drup.2000.0146
  11
  Sulfonamide resistance: Mechanisms and trends
  Skold, Ola
  Drug Resistance Updates (2000), 3 (3), 155-160CODEN: DRUPFW; ISSN:1368-7646. (Harcourt Publishers Ltd.)
  A review with 42 refs. Sulfonamides were the first drugs acting selectively on bacteria which could be used systemically. Today they are infrequently used, in part due to widespread resistance. The target of sulfonamides, and the basis for their selectivity, is the enzyme dihydropteroate synthase (DHPS) in the folic acid pathway. Mammalian cells are not dependent on endogenous synthesis of folic acid and generally lack DHPS. Instead, they have a folate uptake system which most prokaryotes lack. Lab. mutants in the dhps(folP) gene can be easily isolated and show a trade off between sulfonamide resistance and DHPS enzyme performance. Clin. resistant mutants, however, have addnl. compensatory mutations in DHPS that allow it to function normally. In many pathogenic bacteria sulfonamide resistance is mediated by the horizontal transfer of foreign folP or parts of it. Clin. resistance in gram-neg. enteric bacteria is plasmid-borne and is effected by genes encoding alternative drug-resistance variants of the DHPS enzymes. Two such genes, sull and sul2, have been sequenced and are found at roughly the same frequency among clin. isolates. Remarkably, the corresponding DHPS enzymes show pronounced insensitivity to sulfonamides but normal binding to the p-aminobenzoic acid substrate, despite the close structural similarity between substrate and inhibitor.
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12. 12
  Yeaman, M. R. and Yount, N. Y. (2003) Mechanisms of Antimicrobial Peptide Action and Resistance. Pharmacol. Rev. 55, 27– 55, DOI: 10.1124/pr.55.1.2
  12
  Mechanisms of antimicrobial peptide action and resistance
  Yeaman, Michael R.; Yount, Nannette Y.
  Pharmacological Reviews (2003), 55 (1), 27-55CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)
  A review. Antimicrobial peptides have been isolated and characterized from tissues and organisms representing virtually every kingdom and phylum, ranging from prokaryotes to humans. Yet, recurrent structural and functional themes in mechanisms of action and resistance are obsd. among peptides of widely diverse source and compn. Biochem. distinctions among the peptides themselves, target vs. host cells, and the microenvironments in which these counterparts convene, likely provide for varying degrees of selective toxicity among diverse antimicrobial peptide types. Moreover, many antimicrobial peptides employ sophisticated and dynamic mechanisms of action to effect rapid and potent activities consistent with their likely roles in antimicrobial host defense. In balance, successful microbial pathogens have evolved multifaceted and effective countermeasures to avoid exposure to and subvert mechanisms of antimicrobial peptides. A clearer recognition of these opposing themes will significantly advance our understanding of how antimicrobial peptides function in defense against infection. Furthermore, this understanding may provide new models and strategies for developing novel antimicrobial agents, that may also augment immunity, restore potency or amplify the mechanisms of conventional antibiotics, and minimize antimicrobial resistance mechanisms among pathogens. From these perspectives, the intention of this review is to illustrate the contemporary structural and functional themes among mechanisms of antimicrobial peptide action and resistance.
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13. 13
  Brotz, H., Josten, M., Wiedemann, I., Schneider, U., Gotz, F., Bierbaum, G., and Sahl, H. G. (1998) Role of Lipid-Bound Peptidoglycan Precursors in the Formation of Pores by Nisin, Epidermin and Other Lantibiotics. Mol. Microbiol. 30, 317– 327, DOI: 10.1046/j.1365-2958.1998.01065.x
  13
  Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics
  Brotz, Heike; Josten, Michaele; Wiedemann, Imke; Schneider, Ursula; Gotz, Friedrich; Bierbaum, Gabriele; Sahl, Hans-Georg
  Molecular Microbiology (1998), 30 (2), 317-327CODEN: MOMIEE; ISSN:0950-382X. (Blackwell Science Ltd.)
  It is generally assumed that type A lantibiotics primarily kill bacteria by permeabilization of the cytoplasmic membrane. As previous studies had demonstrated that nisin interacts with the membrane-bound peptidoglycan precursors lipid I and lipid II, we presumed that this interaction could play a role in the pore formation process of lantibiotics. Using a thin-layer chromatog. system, the authors found that only nisin and epidermin, but no Pep5, can form a complex with [14C]-lipid II. Lipid II was then purified from Micrococcus luteus and incorporated into carboxyfluorescein-loaded liposomes made of phosphatidylcholine and cholesterol (1:1). Liposomes supplemented with 0.05 or 0.1 mol% of lipid II did not release any marker when treated with Pep5 or epilancin K7 (peptide concns. of up to 5 mol% were tested). In contrast, as little as 0.01 mol% of epidermin and 0.1 mol% of nisin were sufficient to induce rapid marker release; phosphatidylglycerol-contg. liposomes were even more susceptible. Controls with moenomycin-, undecaprenol- or dodecaprenolphosphate-doped liposomes demonstrated the specificity of the lantibiotics for lipid II. These results were correlated with intact cells in an in vivo model. M. luteus and Staphylococcus simulans were depleted of lipid II by preincubation with the lipopeptide ramoplanin and then tested for pore formation. When applied in concns. below the minimal inhibitory concn. (MIC) and up to 5-10 times the MIC, the pore formation by nisin and epidermin was blocked; at higher concns. of the lantibiotics the protective effect of ramoplanin disappeared. These results demonstrate that, in vitro and in vivo, lipid II serves as a docking mol. for nisin and epidermin, but not for Pep5 and epilancin K7, and thereby facilitates the formation of pores in the cytoplasmic membrane.
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14. 14
  Velkov, Y., Thompson, P., Azad, M., Roberts, K., and Bergen, P. (2019) History, Chemistry and Antibacterial Spectrum. In Polymyxin Antibiotics: From Laboratory Bench to Bedside (Li, J., Nation, R., and Kaye, K., Eds.) 1st ed., Vol. 1145, p 17, Spinger Nature, Switzerland AG, DOI: 10.1007/978-3-030-16373-0_3 .
  There is no corresponding record for this reference.
15. 15
  Tang, X.-J., Thibault, P., and Boyd, R. K. (1992) Characterisation of the Tyrocidine and Gramicidin Fractions of the Tyrothricin Complex from Bacillus Brevis Using Liquid Chromatography and Mass Spectrometry. Int. J. Mass Spectrom. Ion Processes 122, 153– 179, DOI: 10.1016/0168-1176(92)87015-7
  15
  Characterization of the tyrocidine and gramicidin fractions of the tyrothricin complex from Bacillus brevis using liquid chromatography and mass spectrometry
  Tang, Xue Jun; Thibault, Pierre; Boyd, Robert K.
  International Journal of Mass Spectrometry and Ion Processes (1992), 122 (), 153-79CODEN: IJMPDN; ISSN:0168-1176.
  The tyrothricin peptide complex, isolated from the fermn. broth of Bacillus brevis, is comprised of a basic fraction of cyclic decapeptides (the tyrocidines) and a neutral fraction composed of linear peptides (the gramicidins). Previously, 5 cyclic compds. (tyrocidines A-E) had been characterized by classical chem. procedures, and an addnl. 5 by M. Barber et al. (1992), who employed tandem mass spectrometric anal. of the crude mixt., together with an interpretative strategy based upon mass shifts related to simple amino acid substitutions. In the present work, initial profiling of the tyrothricin complex, using reverse phase liq. chromatog. (HPLC) coupled directly to tandem mass spectrometry via an ionspray interface, showed that the mixt. is extremely complex. Semi-preparative HPLC provided 32 fractions, some of which were still mixts., amenable to anal. by tandem mass spectrometry using the doubly-protonated peptide precursors produced by ionspray ionization. In this way the 10 previously known tyrocidines were confirmed, and structures of an addnl. 18 cyclic variants established with only minor uncertainties (e.g. present techniques could not distinguish Ile from Leu). Six linear gramicidins were known previously, and were confirmed in the present work. In addn., 3 previously unknown variants, of the Val1-gramicidins A, B and C, were discovered, in which the ethanolamide residue at the C-terminus is replaced by a propanolamide residue.
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16. 16
  Loll, P. J., Upton, E. C., Nahoum, V., Economou, N. J., and Cocklin, S. (2014) The High Resolution Structure of Tyrocidine A Reveals an Amphipathic Dimer. Biochim. Biophys. Acta, Biomembr. 1838, 1199– 1207, DOI: 10.1016/j.bbamem.2014.01.033
  16
  The high resolution structure of tyrocidine A reveals an amphipathic dimer
  Loll, Patrick J.; Upton, Elizabeth C.; Nahoum, Virginie; Economou, Nicoleta J.; Cocklin, Simon
  Biochimica et Biophysica Acta, Biomembranes (2014), 1838 (5), 1199-1207CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Tyrocidine A (I), one of the 1st antibiotics ever to be discovered, is a cyclic decapeptide that binds to membranes of target bacteria, disrupting their integrity. I is active against a broad spectrum of Gram-pos. organisms, and has recently engendered interest as a potential scaffold for the development of new drugs to combat antibiotic-resistant pathogens. Here, the authors present the x-ray crystal structure of I at a resoln. of 0.95 Å. The structure revealed that tyrocidine forms an intimate and highly amphipathic homodimer made up of 4 β-strands that assoc. into a single, highly curved antiparallel β-sheet. The authors used surface plasmon resonance and K+ efflux assays to demonstrate that I bound tightly to mimetics of bacterial membranes with an apparent Kd of 10 μM, and efficiently permeabilized bacterial cells at concns. equal to and below the Kd. Using variant forms of I in which the fluorescent probe p-cyanophenylalanine had been inserted on either the polar or apolar face of the mol., the authors performed fluorescence quenching expts., using both water-sol. and membrane-embedded quenchers. The quenching results, together with the structure, strongly support a membrane assocn. model in which the convex, apolar face of the I β-sheet was oriented toward the membrane interior, while the concave, polar face was presented to the aq. phase.
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17. 17
  Munyuki, G., Jackson, G. E., Venter, G. A., Kover, K. E., Szilagyi, L., Rautenbach, M., Spathelf, B. M., Bhattacharya, B., and van der Spoel, D. (2013) Beta-Sheet Structures and Dimer Models of the Two Major Tyrocidines, Antimicrobial Peptides from Bacillus Aneurinolyticus. Biochemistry 52, 7798– 7806, DOI: 10.1021/bi401363m
  17
  β-Sheet structures and dimer models of the two major tyrocidines, antimicrobial peptides from Bacillus aneurinolyticus
  Munyuki, Gadzikano; Jackson, Graham E.; Venter, Gerhard A.; Kover, Katalin E.; Szilagyi, Laszlo; Rautenbach, Marina; Spathelf, Barbara M.; Bhattacharya, Bhaswati; van der Spoel, David
  Biochemistry (2013), 52 (44), 7798-7806CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  The structures of two major tyrocidines, antibiotic peptides from Bacillus aneurinolyticus, in an aq. environment were studied using NMR spectroscopy, restrained mol. dynamics (MD), CD, and mass spectrometry. TrcA and TrcC formed β-structures in an aq. environment. Hydrophobic and hydrophilic residues were not totally sepd. into nonpolar and polar faces of the peptides, indicating that tyrocidines have low amphipathicity. In all the β-structures, residues Trp4/Phe4 and Orn9 were on the same face. The ability of the peptides to form dimers in aq. environment was studied by replica exchange MD simulations. Both peptides readily dimerize, and predominant complex structures were characterized through cluster anal. The peptides formed dimers by either assocg. sideways or stacking on top of each other. Dimers formed through sideways assocn. were mainly stabilized by hydrogen bonding, while the other dimers were stabilized by hydrophobic interactions. The ability of tyrocidine peptides to form different types of dimers with different orientations suggests that they can form larger aggregates, as well.
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18. 18
  Leussa, A. N.-N. and Rautenbach, M. (2014) Detailed SAR and PCA of the Tyrocidines and Analogues towards Leucocin A-Sensitive and Leucocin A-Resistant Listeria Monocytogenes. Chem. Biol. Drug Des. 84, 543– 557, DOI: 10.1111/cbdd.12344
  18
  Detailed SAR and PCA of tyrocidines and analogs towards leucocin A-sensitive and leucocin A-resistant Listeria monocytogenes
  Leussa, Adrienne Nyango-Nkeh; Rautenbach, Marina
  Chemical Biology & Drug Design (2014), 84 (5), 543-557CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
  The tyrocidines, antimicrobial cyclic decapeptides from Bacillus aneurinolyticus, have potent activity with drug/disinfectant potential, specifically against Listeria monocytogenes. The tyrocidine activity is dependent on an amphipathic balance. Structure-activity relationship (SAR) anal. combined with principal component anal. showed the best activity correlation with hydropathy and solvent accessible vol. (hydrophobicity parameters), Mr and mol. vol. (steric/size parameters), coupled with rigid sequence and charge prerequisites. For potent activity against L. monocytogenes strains, there is a prerequisite for a Tyr or Phe in the (W/F)(w/f)NQ(Y/F/W) sequence of the variable pentapeptide and ornithine (Orn, O) as cationic residue in the conserved V(K/O)LfP pentapeptide, particularly with Trp in the arom. dipeptide moiety of the variable pentapeptide. The roles of Trp and Orn in the tyrocidines were confirmed with the most active peptide, tyrocidine B (TrcB) contg. Orn and a Trp-D-Phe in the arom. dipeptide moiety. However, a novel analog with a trimethylated ornithine and Phe-D-Phe showed an activity rivalling that of TrcB. The results emphasize that activity is dictated by an interplay between the character of the arom. residues in the variable pentapeptide and the cationic residue. Any residue change resulting in tighter membrane/cell wall interaction is likely to trap tyrocidines and impede their mechanism of action.
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19. 19
  Spathelf, B. M. and Rautenbach, M. (2009) Anti-Listerial Activity and Structure-Activity Relationships of the Six Major Tyrocidines, Cyclic Decapeptides from Bacillus Aneurinolyticus. Bioorg. Med. Chem. 17, 5541– 5548, DOI: 10.1016/j.bmc.2009.06.029
  19
  Anti-listerial activity and structure-activity relationships of the six major tyrocidines, cyclic decapeptides from Bacillus aneurinolyticus
  Spathelf, Barbara M.; Rautenbach, Marina
  Bioorganic & Medicinal Chemistry (2009), 17 (15), 5541-5548CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  Six major tyrocidines, purified from the antibiotic tyrothricin complex produced by Bacillus aneurinolyticus, showed significant lytic and growth inhibitory activity towards the Gram-pos. bacteria Micrococcus luteus and Listeria monocytogenes, but not against the Gram-neg. Escherichia coli. The isolated natural tyrocidines were more active against the leucocin A (antimicrobial peptide) resistant strain, L. monocytogenes B73-MR1, than the sensitive L. monocytogenes B73 strain. Remarkably similar structure-activity trends toward the three Gram-pos. bacteria were found between growth inhibition and different physicochem. parameters (soln. amphipathicity, theor. lipophilicity, side-chain surface area and mass-over-charge ratio).
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20. 20
  Wenzel, M., Rautenbach, M., Vosloo, J. A., Siersma, T., Aisenbrey, C. H. M., Zaitseva, E., Laubscher, W. E., van Rensburg, W., Behrends, J., Bechinger, B., and Hamoen, L. W. (2018) The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S. mBio 9, e00802-18 DOI: 10.1128/mBio.00802-18
  There is no corresponding record for this reference.
21. 21
  Palm, J., Fuchs, K., Stammer, H., Schumacher-Stimpfl, A., and Milde, J. (2018) Efficacy and Safety of a Triple Active Sore Throat Lozenge in the Treatment of Patients with Acute Pharyngitis: Results of a Multi-Centre, Randomised, Placebo-Controlled, Double-Blind, Parallel-Group Trial (DoriPha). Int. J. Clin. Pract. 72, e13272 DOI: 10.1111/ijcp.13272
  There is no corresponding record for this reference.
22. 22
  Bosscha, M. I., van Dissel, J. T., Kuijper, E. J., Swart, W., and Jager, M. J. (2004) The Efficacy and Safety of Topical Polymyxin B, Neomycin and Gramicidin for Treatment of Presumed Bacterial Corneal Ulceration. Br. J. Ophthalmol. 88, 25– 28, DOI: 10.1136/bjo.88.1.25
  22
  The efficacy and safety of topical polymyxin B, neomycin and gramicidin for treatment of presumed bacterial corneal ulceration
  Bosscha M I; van Dissel J T; Kuijper E J; Swart W; Jager M J
  The British journal of ophthalmology (2004), 88 (1), 25-8 ISSN:0007-1161.
  AIM: To evaluate the clinical efficacy and safety of topical polymyxin B, neomycin, and gramicidin for the treatment of suspected bacterial corneal ulceration at the Leiden University Medical Center. METHODS: Patients with a diagnosis of a suspected bacterial corneal ulcer between April 1995 and February 2002 were retrospectively identified and reviewed; clinical and microbiological features and response to therapy were analysed. All patients were treated with Polyspectran eye drops. RESULTS: In total, 91 patients were included in this analysis. Bacteriological cultures of 46 patients (51%) were positive and revealed 51 microorganisms. Staphylococcus aureus (29.4%) and Pseudomonas aeruginosa (23.5%) were the most frequently encountered bacteria. Eighteen patients switched therapy before complete healing of the corneal ulceration, four patients were lost to follow up. Of the 69 patients who completed Polyspectran treatment, re-epithelialisation occurred in 68 patients (99%) and on average took 12.6 (median 8) days. Among 91 patients, there were four perforations and one evisceration. Seven toxic or allergic reactions were reported. CONCLUSION: This study shows that the combination of polymyxin B, neomycin, and gramicidin is an effective and safe treatment of suspected corneal ulceration.
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23. 23
  Jia, J., Zhu, F., Ma, X., Cao, Z. W., Li, Y. X., and Chen, Y. Z. (2009) Mechanisms of Drug Combinations: Interaction and Network Perspectives. Nat. Rev. Drug Discovery 8, 111, DOI: 10.1038/nrd2683
  23
  Mechanisms of drug combinations: interaction and network perspectives
  Jia, Jia; Zhu, Feng; Ma, Xiaohua; Cao, Zhiwei W.; Li, Yixue X.; Chen, Yu Zong
  Nature Reviews Drug Discovery (2009), 8 (2), 111-128CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
  A review. Understanding the mol. mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous anal. methods and for which relevant mol. interaction profiles of the drugs involved are available. Anal. of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of mol. interaction profiles in the discovery of novel multicomponent therapies.
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24. 24
  Reddy, A. S. and Zhang, S. (2013) Polypharmacology: Drug Discovery for the Future. Expert Rev. Clin. Pharmacol. 6, 41– 47, DOI: 10.1586/ecp.12.74
  24
  Polypharmacology: drug discovery for the future
  Reddy, A. Srinivas; Zhang, Shuxing
  Expert Review of Clinical Pharmacology (2013), 6 (1), 41-47CODEN: ERCPAG; ISSN:1751-2433. (Expert Reviews Ltd.)
  A review. In recent years, even with remarkable scientific advancements and a significant increase of global research and development spending, drugs are frequently withdrawn from markets. This is primarily due to their side effects or toxicities. Drug mols. often interact with multiple targets, coined as polypharmacol., and the unintended drug-target interactions could cause side effects. Polypharmacol. remains one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective, but less toxic, therapeutic agents. This review outlines the latest progress and challenges in polypharmacol. studies.
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25. 25
  Müller, A., Wenzel, M., Strahl, H., Grein, F., Saaki, T. N. V, Kohl, B., Siersma, T., Bandow, J. E., Sahl, H.-G., Schneider, T., and Hamoen, L. W. (2016) Daptomycin Inhibits Cell Envelope Synthesis by Interfering with Fluid Membrane Microdomains. Proc. Natl. Acad. Sci. U. S. A. 113, E7077– E7086, DOI: 10.1073/pnas.1611173113
  25
  Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains
  Mueller, Anna; Wenzel, Michaela; Strahl, Henrik; Grein, Fabian; Saaki, Terrens N. V.; Kohl, Bastian; Siersma, Tjalling; Bandow, Julia E.; Sahl, Hans-Georg; Schneider, Tanja; Hamoen, Leendert W.
  Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (45), E7077-E7086CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Daptomycin is a highly efficient last-resort antibiotic that targets the bacterial cell membrane. Despite its clin. importance, the exact mechanism by which daptomycin kills bacteria is not fully understood. Different expts. have led to different models, including (i) blockage of cell wall synthesis, (ii) membrane pore formation, and (iii) the generation of altered membrane curvature leading to aberrant recruitment of proteins. To det. which model is correct, the authors carried out a comprehensive mode-of-action study using the model organism Bacillus subtilis and different assays, including proteomics, ionomics, and fluorescence light microscopy. The authors found that daptomycin causes a gradual decrease in membrane potential but does not form discrete membrane pores. Although the authors found no evidence for altered membrane curvature, the authors confirmed that daptomycin inhibits cell wall synthesis. Interestingly, using different fluorescent lipid probes, the authors showed that binding of daptomycin led to a drastic rearrangement of fluid lipid domains, affecting overall membrane fluidity. Importantly, these changes resulted in the rapid detachment of the membrane-assocd. lipid II synthase MurG and the phospholipid synthase PlsX. Both proteins preferentially colocalize with fluid membrane microdomains. Delocalization of these proteins presumably is a key reason why daptomycin blocks cell wall synthesis. Finally, clustering of fluid lipids by daptomycin likely causes hydrophobic mismatches between fluid and more rigid membrane areas. This mismatch can facilitate proton leakage and may explain the gradual membrane depolarization obsd. with daptomycin. Targeting of fluid lipid domains has not been described before for antibiotics and adds another dimension to the authors' understanding of membrane-active antibiotics.
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26. 26
  Hachmann, A. B., Sevim, E., Gaballa, A., Popham, D. L., Antelmann, H., and Helmann, J. D. (2011) Reduction in Membrane Phosphatidylglycerol Content Leads to Daptomycin Resistance in Bacillus Subtilis. Antimicrob. Agents Chemother. 55, 4326– 4337, DOI: 10.1128/AAC.01819-10
  26
  Reduction in membrane phosphatidylglycerol content leads to daptomycin resistance in Bacillus subtilis
  Hachmann, Anna-Barbara; Sevim, Elif; Gaballa, Ahmed; Popham, David L.; Antelmann, Haike; Helmann, John D.
  Antimicrobial Agents and Chemotherapy (2011), 55 (9), 4326-4337CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  Daptomycin (DAP) is a cyclic lipopeptide that disrupts the functional integrity of the cell membranes of Gram-pos. bacteria in a Ca2+-dependent manner. Here, the authors present genetic, genomic, and phenotypic analyses of an evolved DAP-resistant isolate, DapR1, from the model bacterium Bacillus subtilis 168. DapR1 was obtained by serial passages with increasing DAP concns., is 30-fold more resistant than the parent strain, and displays cross-resistance to vancomycin, moenomycin, and bacitracin. DapR1 is characterized by aberrant septum placement, notably thickened peptidoglycan at the cell poles, and pleiotropic alterations at both the transcriptome and proteome levels. Genome sequencing of DapR1 revealed 44 point mutations, 31 of which change protein sequences. An intermediate isolate that was 20-fold more resistant to DAP than the wild type had only three of these point mutations: mutations affecting the cell shape modulator gene mreB, the stringent response gene relA, and the phosphatidylglycerol synthase gene pgsA. Genetic reconstruction studies indicated that the pgsA(A64V) allele is primarily responsible for DAP resistance. Allelic replacement with wild-type pgsA restored DAP sensitivity to wild-type levels. The addnl. point mutations in the evolved strain may contribute further to DAP resistance, serve to compensate for the deleterious effects of altered membrane compn., or represent neutral changes. These results suggest a resistance mechanism by which reduced levels of phosphatidylglycerol decrease the net neg. charge of the membrane, thereby weakening interaction with the pos. charged Ca2+-DAP complex.
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27. 27
  Reynolds, P. E. (1989) Structure, Biochemistry and Mechanism of Action of Glycopeptide Antibiotics. Eur. J. Clin. Microbiol. Infect. Dis. 8, 943– 950, DOI: 10.1007/BF01967563
  27
  Structure, biochemistry, and mechanism of action of glycopeptide antibiotics
  Reynolds, P. E.
  European Journal of Clinical Microbiology & Infectious Diseases (1989), 8 (11), 943-50CODEN: EJCDEU; ISSN:0934-9723.
  A review with 27 refs. discussing the unique mechanism of action by which peptidoglycan antibiotics inhibit a late stage in bacterial cell wall peptidoglycan synthesis.
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28. 28
  Singh, M., Chang, J., Coffman, L., and Kim, S. J. (2017) Hidden Mode of Action of Glycopeptide Antibiotics: Inhibition of Wall Teichoic Acid Biosynthesis. J. Phys. Chem. B 121, 3925– 3932, DOI: 10.1021/acs.jpcb.7b00324
  28
  Hidden Mode of Action of Glycopeptide Antibiotics: Inhibition of Wall Teichoic Acid Biosynthesis
  Singh, Manmilan; Chang, James; Coffman, Lauryn; Kim, Sung Joon
  Journal of Physical Chemistry B (2017), 121 (16), 3925-3932CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
  Glycopeptide antibiotics inhibit the peptidoglycan biosynthesis in Gram-pos. bacteria by targeting lipid II. This prevents the recycling of bactoprenol phosphate, the lipid transporter that is shared by peptidoglycan and wall teichoic acid biosyntheses. In this study, we investigate the effects of glycopeptide antibiotics on peptidoglycan and wall teichoic acid biosynthesis. The incorporation of D-[1-13C]alanine, D-[15N]alanine, and L-[1-13C]lysine into peptidoglycan and wall teichoic acid in intact whole cells of Staphylococcus aureus were measured using 13C{15N} and 15N{13C} rotational-echo double resonance NMR. S. aureus treated with oritavancin and vancomycin at sub-minimal inhibitory concns. exhibit a large redn. in D-Ala incorporation into wall teichoic acid, but without changes to the peptidoglycan crosslinks or the stem-links. Thus, sequestration of bactoprenol phosphate by glycopeptide antibiotics resulted in inhibition of D-Ala incorporation into the wall teichoic acid prior to the inhibition of peptidoglycan biosynthesis. Our finding shows that S. aureus respond to glycopeptide-induced cell wall stress by routing all available D-Ala to the peptidoglycan biosynthesis, at the cost of reducing the wall teichoic acid biosynthesis.
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29. 29
  Stone, K. J. and Strominger, J. L. (1971) Mechanism of Action of Bacitracin: Complexation with Metal Ion and C55-Isoprenyl Pyrophosphate. Proc. Natl. Acad. Sci. U. S. A. 68, 3223– 3227, DOI: 10.1073/pnas.68.12.3223
  29
  Mechanism of action of bacitracin. Complexation with metal ion and C55-isoprenyl pyrophosphate
  Stone, K. John; Strominger, Jack L.
  Proceedings of the National Academy of Sciences of the United States of America (1971), 68 (12), 3223-7CODEN: PNASA6; ISSN:0027-8424.
  Bacitracin inhibition of the enzymic dephosphorylation of C55-isoprenyl pyrophosphate [31867-59-1] was abolished by the addn. of chelating agents such as EDTA [60-00-4] (.sim.10-4M). If the chelating agent is added after a preincubation of bacitracin with a divalent cation (magnesium ion [7439-95-4], calcium ion [7440-70-2], etc.) and the lipid substrate, then its addn. has little effect,indicating that bacitracin, metal ion, and C55-isoprenyl pyrophosphate form a complex. Monovalent cations are ineffective in complex formation. The metal ion may serve as a bridge between the antibiotic and substrate.
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30. 30
  Tu, Y. and McCalla, D. R. (1975) Effect of Activated Nitrofurans on DNA. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 402, 142– 149, DOI: 10.1016/0005-2787(75)90032-5
  30
  Effect of activated nitrofurans on DNA
  Tu, Yu; McCalla, D. R.
  Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1975), 402 (2), 142-9CODEN: BBNPAS; ISSN:0005-2787.
  Enzymically activated nitrofurazone (I) [59-87-0] reacted with covalently closed circular DNA (derived from Escherichia coli minicells carrying λdv) to give ≥2 kinds of damage: breaks which were detected on neutral sucrose gradients and alkali-labile lesions in DNA which were converted to breaks when the DNA was subsequently treated with alkali. DNA, isolated from minicells exposed to the drug, also contained lesions which were converted to breaks upon treatment with endonuclease prepns. obtained from Micrococcus luteus. Minicells repaired both breaks and nuclease-susceptible lesions within 2 hr but did not repair alkali labile lesions within that time. Expts. with 3 other nitrofurans showed that there were considerable differences in the degree to which DNA was damaged by activated metabolites of various derivs. and that the potency of the compds. as mutagens and carcinogens was correlated with the amt. of damage caused to minicell DNA.
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31. 31
  Wenzel, M., Dekker, M. P., Wang, B., Burggraaf, M. J., Bitter, W., van Weering, J. R. T., and Hamoen, L. W. (2019) New Flat Embedding Method for Transmission Electron Microscopy Reveals an Unknown Mechanism of Tetracycline. bioRxiv 820191, DOI: 10.1101/820191
  There is no corresponding record for this reference.
32. 32
  Brötz-Oesterhelt, H., Beyer, D., Kroll, H.-P., Endermann, R., Ladel, C., Schroeder, W., Hinzen, B., Raddatz, S., Paulsen, H., Henninger, K., Bandow, J. E., Sahl, H.-G., and Labischinski, H. (2005) Dysregulation of Bacterial Proteolytic Machinery by a New Class of Antibiotics. Nat. Med. 11, 1082– 1087, DOI: 10.1038/nm1306
  32
  Dysregulation of bacterial proteolytic machinery by a new class of antibiotics
  Brotz-Oesterhelt Heike; Beyer Dieter; Kroll Hein-Peter; Endermann Rainer; Ladel Christoph; Schroeder Werner; Hinzen Berthold; Raddatz Siegfried; Paulsen Holger; Henninger Kerstin; Bandow Julia E; Sahl Hans-Georg; Labischinski Harald
  Nature medicine (2005), 11 (10), 1082-7 ISSN:1078-8956.
  Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.
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33. 33
  Sass, P., Josten, M., Famulla, K., Schiffer, G., Sahl, H.-G., Hamoen, L., and Brotz-Oesterhelt, H. (2011) Antibiotic Acyldepsipeptides Activate ClpP Peptidase to Degrade the Cell Division Protein FtsZ. Proc. Natl. Acad. Sci. U. S. A. 108, 17474– 17479, DOI: 10.1073/pnas.1110385108
  33
  Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ
  Sass, Peter; Josten, Michaele; Famulla, Kirsten; Schiffer, Guido; Sahl, Hans-Georg; Hamoen, Leendert; Broetz-Oesterhelt, Heike
  Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (42), 17474-17479, S17474/1-S17474/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The worldwide spread of antibiotic-resistant bacteria has lent urgency to the search for antibiotics with new modes of action that are devoid of preexisting cross-resistances. We previously described a unique class of acyldepsipeptides (ADEPs) that exerts prominent antibacterial activity against Gram-pos. pathogens including streptococci, enterococci, as well as multi-drug-resistant Staphylococcus aureus. Here, we report that ADEP prevents cell division in Gram-pos. bacteria and induces strong filamentation of rod-shaped Bacillus subtilis and swelling of coccoid S. aureus and Streptococcus pneumoniae. It emerged that ADEP treatment inhibits septum formation at the stage of Z-ring assembly, and that central cell division proteins delocalize from midcell positions. Using in vivo and in vitro studies, we show that the inhibition of Z-ring formation is a consequence of the proteolytic degrdn. of the essential cell division protein FtsZ. ADEP switches the bacterial ClpP peptidase from a regulated to an uncontrolled protease, and it turned out that FtsZ is particularly prone to degrdn. by the ADEP-CIpP complex. By preventing cell division, ADEP inhibits a vital cellular process of bacteria that is not targeted by any therapeutically applied antibiotic so far. Their unique multi-faceted mechanism of action and antibacterial potency makes them promising lead structures for future antibiotic development.
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34. 34
  Deoghare, S. (2013) Bedaquiline: A New Drug Approved for Treatment of Multidrug-Resistant Tuberculosis. Indian J. Pharmacol. 45, 536– 537, DOI: 10.4103/0253-7613.117765
  34
  Bedaquiline: a new drug approved for treatment of multidrug-resistant tuberculosis
  Deoghare Shashank
  Indian journal of pharmacology (2013), 45 (5), 536-7 ISSN:.
  There is no expanded citation for this reference.
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35. 35
  Chopra, I. and Roberts, M. (2001) Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance. Microbiol. Mol. Biol. Rev. 65, 232– 60, DOI: 10.1128/MMBR.65.2.232-260.2001
  35
  Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance
  Chopra, Ian; Roberts, Marilyn
  Microbiology and Molecular Biology Reviews (2001), 65 (2), 232-260CODEN: MMBRF7; ISSN:1092-2172. (American Society for Microbiology)
  A review is given. Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-pos. and gram-neg. bacteria, chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites. They are inexpensive antibiotics, which were used extensively in the prophylaxis and therapy of human and animal infections and also at subtherapeutic levels in animal feed as growth promoters. The 1st tetracycline-resistant bacterium, Shigella dysenteriae, was isolated in 1953. Tetracycline resistance now occurs in an increasing no. of pathogenic, opportunistic, and commensal bacteria. The presence of tetracycline-resistant pathogens limits the use of these agents in treatment of disease. Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Many of these genes are assocd. with mobile plasmids or transposons and can be distinguished from each other using mol. methods including DNA-DNA hybridization with oligonucleotide probes and DNA sequencing. A limited no. of bacteria acquire resistance by mutations, which alter the permeability of the outer membrane porins and/or lipopolysaccharides in the outer membrane, change the regulation of innate efflux systems, or alter the 16S rRNA. New tetracycline derivs. are being examd., although their role in treatment is not clear. Changing the use of tetracyclines in human and animal health as well as in food prodn. is needed if the authors are to continue to use this class of broad-spectrum antimicrobials through the present century.
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36. 36
  Teuber, M. and Bader, J. (1976) Action of Polymyxin B on Bacterial Membranes. Binding Capacities for Polymyxin B of Inner and Outer Membranes Isolated from Salmonella Typhimurium G30. Arch. Microbiol. 109, 51– 58, DOI: 10.1007/BF00425112
  36
  Action of polymyxin B on bacterial membranes. Binding capacities for polymyxin B of inner and outer membranes isolated from Salmonella typhimurium G30
  Teuber, Michael; Bader, Johann
  Archives of Microbiology (1976), 109 (1-2), 51-8CODEN: AMICCW; ISSN:0302-8933.
  Polymyxin B sulfate [1405-20-5] was absorbed within 60 sec by isolated inner (cytoplasmic) and outer membranes from S. typhimurium. The sigmoidal binding isotherms indicated satn. of inner and outer membranes with approx. 30 and 60 nmoles polymyxin B bound per mg membrane, resp. Based on the known lipid contents of these membranes, a calcn. of the theor. binding capacities yielded almost identical values if lipopolysaccharide, phosphatidylglycerol, and cardiolipin are assumed to function as the actual binding sites for the antibiotic in the isolated membranes. The excellent agreement between theor. evaluation and exptl. detn. of polymyxin B-binding capacities indicated that the named anionic compds. are the chemoreceptors for the cationic antibiotic. This was further substantiated by very similar binding and killing kinetics of polymyxin B.
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37. 37
  Bohg, A. and Ristow, H. (1987) Tyrocidine-Induced Modulation of the DNA Conformation in Bacillus Brevis. Eur. J. Biochem. 170, 253– 258, DOI: 10.1111/j.1432-1033.1987.tb13693.x
  37
  Tyrocidine-induced modulation of the DNA conformation in Bacillus brevis
  Bohg, Anne; Ristow, Hansjuergen
  European Journal of Biochemistry (1987), 170 (1/2), 253-8CODEN: EJBCAI; ISSN:0014-2956.
  Using the [3H]trimethylpsoralen photobinding method, a decrease in unrestrained torsional tension of DNA was detected in B. brevis when they had entered the sporulation phase. This decrease in superhelicity was found in cells which synthesized the peptide antibiotic tyrocidine and which were stimulated to sporulate. Fluctuations in superhelicity probably reflect a highly complicated picture of tension-relaxing and tension-inducing activities. Addn. of tyrocidine to vegetative cells reduced by one-half the torsional tension from DNA, whereas ethidium bromide relaxes DNA completely. Cross-links between DNA and tyrocidine were introduced with UV light in vitro and in vivo, indicating that the modulation of the DNA conformation in the cell may in fact be due to a DNA-tyrocidine interaction. In a growing B. brevis culture exogenous [3H]tyorcidine could only be photobound to DNA after the cells had entered the sporulation phase. These results could mean that the peptide antibiotic tyrocidine is active in B. brevis on the DNA level as one regulatory factor controlling DNA functions.
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38. 38
  Ristow, H., Schazschneider, B., Vater, J., and Kleinkauf, H. (1975) Some Characteristics of the DNA-Tyrocidine Complex and a Possible Mechanism of the Gramicidin Action. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 414, 1– 8, DOI: 10.1016/0005-2787(75)90120-3
  38
  Characteristics of the DNA-tyrocidine complex and a possible mechanism of the gramicidin action
  Ristow, H.; Schazschneider, B.; Vater, J.; Kleinkauf, H.
  Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1975), 414 (1), 1-8CODEN: BBNPAS; ISSN:0005-2787.
  The cyclic peptide antibiotic tyrocidine which is known to inhibit RNA synthesis in vitro by forming a complex with the DNA induced hypochromicity of the DNA. The complex dissocd. at elevated temps. which are below the melting temp. of the DNA. The linear peptide antibiotic gramicidin which is known to reverse the inhibitory effect of tyrocidine did not bind to DNA and did not induce hypochromicity of the DNA. However, the DNA-tyrocidine complex dissocd. at lower temps. when gramicidin was present. Thus gramicidin apparently weakens the binding of tyrocidine to DNA. The presence of DNA quenched the fluorescence of tyrocidine but not that of gramicidin. This quenching of tyrocidine fluorescence was reduced in the presence of gramicidin. Tyrocidine inhibited transcription of single-stranded DNA as well. This inhibition was also reversed by gramicidin. Thus, the action of the peptides is not dependent on a double-stranded DNA conformation.
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39. 39
  Weinkle, A. P., Doktor, V., and Emer, J. (2015) Update on the Management of Rosacea. Clin., Cosmet. Invest. Dermatol. 8, 159– 177, DOI: 10.2147/CCID.S58940
  39
  Update on the management of rosacea
  Weinkle, Allison P.; Doktor, Vladyslava; Emer, Jason
  Clinical, Cosmetic and Investigational Dermatology (2015), 8 (), 159-177CODEN: CCIDCL; ISSN:1178-7015. (Dove Medical Press Ltd.)
  Refining diagnostic criteria has identified key characteristics differentiating rosacea, a chronic skin disorder, from other common cutaneous inflammatory conditions. The current classification system developed by the National Rosacea Society Expert Committee consists of erythematotelangiectatic, papulopustular, phymatous, and ocular subtypes. Each subtype stands as a unique entity among a spectrum, with characteristic symptoms and phys. findings, along with an intricate pathophysiol. The main treatment modalities for rosacea include topical, systemic, laser, and light therapies. Topical brimonidine tartrate gel and calcineurin inhibitors are at the forefront of topical therapies, alone or in combination with traditional therapies such as topical metronidazole or azelaic acid and oral tetracyclines or isotretinoin. Vascular laser and intense pulsed light therapies are beneficial for the erythema and telangiectasia, as well as the symptoms (itching, burning, pain, stinging, swelling) of rosacea. Injectable botulinum toxin, topical ivermectin, and microsecond long-pulsed neodymium-yttrium aluminum garnet laser are emerging therapies that may prove to be extremely beneficial in the future. Once a debilitating disorder, rosacea has become a well known and manageable entity in the setting of numerous emerging therapeutic options. Herein, we describe the treatments currently available and give our opinions regarding emerging and combination therapies.
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40. 40
  Del Rosso, J. Q. and Schmidt, N. F. (2010) A Review of the Anti-Inflammatory Properties of Clindamycin in the Treatment of Acne Vulgaris. Cutis 85, 15– 24
  40
  A review of the anti-inflammatory properties of clindamycin in the treatment of acne vulgaris
  Del Rosso James Q; Schmidt Nicholas F
  Cutis (2010), 85 (1), 15-24 ISSN:0011-4162.
  This article reviews anti-inflammatory properties of clindamycin, which is often used topically for the management of acne vulgaris, usually in combination with other agents. The efficacy of clindamycin in acne treatment has been shown to be sustained for more than 3 decades. It is likely that anti-inflammatory effects play an important role in the therapeutic activity of topical clindamycin.
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41. 41
  Goihman-Yahr, M., Pari, T., George, S., Jacob, M., Chandi, S. M., Pulimood, S., and Rajagopalan, B. (1996) Malignant Pyoderma Responding to Clofazimine. Int. J. Dermatol. 35, 757, DOI: 10.1111/j.1365-4362.1996.tb00660.x
  There is no corresponding record for this reference.
42. 42
  Seukeran, D. C., Stables, G. I., Cunliffe, W. J., and Sheehan-Dare, R. A. (1999) The Treatment of Acne Agminata with Clofazimine. Br. J. Dermatol. 141, 596– 597, DOI: 10.1046/j.1365-2133.1999.03084.x
  42
  The treatment of acne agminata with clofazimine
  Seukeran D C; Stables G I; Cunliffe W J; Sheehan-Dare R A
  The British journal of dermatology (1999), 141 (3), 596-7 ISSN:0007-0963.
  There is no expanded citation for this reference.
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43. 43
  Gomez-De la Fuente, E., del Rio, R., Rodriguez, M., Guerra, A., Rodriguez-Peralto, J. L., and Iglesias, L. (2000) Granuloma Faciale Mimicking Rhinophyma: Response to Clofazimine. Acta Derm.-Venereol. 80, 144
  43
  Granuloma faciale mimicking rhinophyma: response to clofazimine
  Gomez-de la Fuente E; del Rio R; Rodriguez M; Guerra A; Rodriguez-Peralto J L; Iglesias L
  Acta dermato-venereologica (2000), 80 (2), 144 ISSN:0001-5555.
  There is no expanded citation for this reference.
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44. 44
  Prendiville, J. S., Logan, R. A., and Russell-Jones, R. (1988) A Comparison of Dapsone with 13-Cis Retinoic Acid in the Treatment of Nodular Cystic Acne. Clin. Exp. Dermatol. 13, 67– 71, DOI: 10.1111/j.1365-2230.1988.tb00659.x
  44
  A comparison of dapsone with 13-cis retinoic acid in the treatment of nodular cystic acne
  Prendiville J S; Logan R A; Russell-Jones R
  Clinical and experimental dermatology (1988), 13 (2), 67-71 ISSN:0307-6938.
  There is no expanded citation for this reference.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M7gs1Cmuw%253D%253D&md5=457b249663806af897713ab7110a3d23
45. 45
  Tan, B. B., Lear, J. T., and Smith, A. G. (1997) Acne Fulminans and Erythema Nodosum during Isotretinoin Therapy Responding to Dapsone. Clin. Exp. Dermatol. 22, 26– 27, DOI: 10.1046/j.1365-2230.1997.1830600.x
  45
  Acne fulminans and erythema nodosum during isotretinoin therapy responding to dapsone
  Tan B B; Lear J T; Smith A G
  Clinical and experimental dermatology (1997), 22 (1), 26-7 ISSN:0307-6938.
  Acne vulgaris is very common, 85% of teenagers being affected at any one time. In most cases, the disease is mild and patients do not present to the dermatologist. Most are instead treated with over-the-counter products and conventional treatment such as peeling agents or topical and systemic antibiotics. Isotretinoin has revolutionized the treatment of severe acne unresponsive to oral antibiotics. Explosive and very severe acne such as pyoderma faciale, acne conglobata and acne fulminans are rare, the features that distinguish acne fulminans from the other conditions being systemic upset with fever, joint pain, malaise and leucocytosis, while there have been two reports of the condition associated with erythema nodosum. The recommended treatment for acne fulminans is a combination of oral steroids and systemic antibiotics, isotretinoin probably not being the treatment of choice. We now report a patient who developed acne fulminans and erythema nodosum within 3 weeks of starting isotretinoin and then responded to dapsone without oral steroids.
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46. 46
  Lopez-Boado, Y. S. and Rubin, B. K. (2008) Macrolides as Immunomodulatory Medications for the Therapy of Chronic Lung Diseases. Curr. Opin. Pharmacol. 8, 286– 291, DOI: 10.1016/j.coph.2008.01.010
  46
  Macrolides as immunomodulatory medications for the therapy of chronic lung diseases
  Lopez-Boado, Yolanda S.; Rubin, Bruce K.
  Current Opinion in Pharmacology (2008), 8 (3), 286-291CODEN: COPUBK; ISSN:1471-4892. (Elsevier B.V.)
  A review. Macrolide antibiotics have potent immunomodulatory activity. The spectrum of action of these antibiotics extends to regulation of leukocyte function and prodn. of inflammatory mediators, control of mucus hypersecretion, resoln. of inflammation, and modulation of host defense mechanisms. Macrolides are now being used or investigated to treat chronic lung inflammatory diseases, including diffuse panbronchiolitis (DPB), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and asthma. Intense research is ongoing to further elucidate the targets and mechanism/s of action of macrolides in eukaryotic cells. In this paper, we review recent findings on novel effects of macrolides on epithelial barrier function and resoln. of inflammation, which may shed light on the mechanisms underlying the beneficial effects of macrolides in the clinic.
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47. 47
  Keicho, N. and Kudoh, S. (2002) Diffuse Panbronchiolitis: Role of Macrolides in Therapy. Am. J. Respir. Med. 1, 119– 131, DOI: 10.1007/BF03256601
  47
  Diffuse panbronchiolitis: role of macrolides in therapy
  Keicho, Naoto; Kudoh, Shoji
  American Journal of Respiratory Medicine (2002), 1 (2), 119-131CODEN: AJRMAG; ISSN:1175-6365. (Adis International Ltd.)
  A review. Diffuse panbronchiolitis (DPB) is characterized by chronic sinobronchial infection and diffuse bilateral micronodular pulmonary lesions consisting of inflammatory cells. Studies on disease etiol. point to a genetic predisposition unique to Asians. Early therapy for DPB was largely symptomatic. The advent of macrolide antibiotics, including erythromycin, roxithromycin and clarithromycin, has strikingly changed disease prognosis. Low-dose, long-term macrolide therapy for DPB originated from detailed observations of response to therapy in a single patient. The bactericidal activity of macrolides, particularly erythromycin, is not a significant factor for their clin. efficacy in DPB. Firstly, irresp. of bacterial clearance, clin. improvement is obsd. in patients treated with erythromycin. Secondly, even in cases with bacterial superinfection with Pseudomonas aeruginosa resistant to macrolides, treatment has proved effective. Thirdly, the recommended dosage of macrolides produces peak levels in tissue that are below the min. inhibitory concns. for major pathogenic bacteria that colonize the airway. In the last two decades, the possible mechanism underlying the effectiveness of macrolide therapy has been extensively studied. The proposed mechanism of action includes inhibition of excessive mucus and water secretion from the airway epithelium, inhibition of neutrophil accumulation in the large airway, inhibition of lymphocyte and macrophage accumulation around the small airway, and modulation of bacterial virulence. The great success of macrolide therapy in diffuse panbronchiolitis may extend its application to the treatment of other chronic inflammatory disorders. If the anti-inflammatory activity of macrolides is independent of their bactericidal effect, new anti-inflammatory macrolides without antimicrobial activity should be developed to minimize emergence of macrolide-resistant micro-organisms.
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48. 48
  Pradhan, S., Madke, B., Kabra, P., and Singh, A. L. (2016) Anti-Inflammatory and Immunomodulatory Effects of Antibiotics and Their Use in Dermatology. Indian J. Dermatol. 61, 469– 481, DOI: 10.4103/0019-5154.190105
  48
  Anti-inflammatory and Immunomodulatory Effects of Antibiotics and Their Use in Dermatology
  Pradhan Swetalina; Madke Bhushan; Kabra Poonam; Singh Adarsh Lata
  Indian journal of dermatology (2016), 61 (5), 469-81 ISSN:.
  Antibiotics (antibacterial, antiviral, and antiparasitic) are class of drugs which result in either killing or inhibiting growth and multiplication of infectious organisms. Antibiotics are commonly prescribed by all specialties for treatment of infections. However, antibiotics have hitherto immunomodulatory and anti-inflammatory properties and can be exploited for various noninfectious dermatoses. Dermatologists routinely prescribe antibiotics in treatment of various noninfectious disorders. This study will review anti-inflammatory and immunomodulatory effects of antibiotics and their use in dermatology.
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49. 49
  Schaeverbeke, T., Lequen, L., de Barbeyrac, B., Labbe, L., Bebear, C. M., Morrier, Y., Bannwarth, B., Bebear, C. M., and Dehais, J. (1998) Propionibacterium Acnes Isolated from Synovial Tissue and Fluid in a Patient with Oligoarthritis Associated with Acne and Pustulosis. Arthritis Rheum. 41, 1889– 1893, DOI: 10.1002/1529-0131(199810)41:10<1889::AID-ART23>3.0.CO;2-F
  49
  Propionibacterium acnes isolated from synovial tissue and fluid in a patient with oligoarthritis associated with acne and pustulosis
  Schaeverbeke T; Lequen L; de Barbeyrac B; Labbe L; Bebear C M; Morrier Y; Bannwarth B; Bebear C; Dehais J
  Arthritis and rheumatism (1998), 41 (10), 1889-93 ISSN:0004-3591.
  This report describes the case of a patient with a 14-month course of severe oligoarthritis associated with acne. Pure cultures of Propionibacterium acnes were isolated from synovial tissue and synovial fluid specimens collected from the same joint after a 4-month interval. After 2 months of treatment with roxithromycin 300 mg/day, rifampicin 1,200 mg/day, and a nonsteroidal antiinflammatory drug (NSAID), followed by 4 months of treatment with azithromycin 1 gm/week and an NSAID, the synovitis persisted. Cultures of skin lesions and synovial fluid at this time were negative. Although P acnes has previously been isolated from bone specimens obtained from patients with osteitis associated with acne, this is the first report of the isolation of this microorganism from the synovial tissue of a patient with arthritis associated with acne. Our findings raise the question of the role of P acnes in the pathogenesis of arthritis associated with acne.
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50. 50
  Nishimuta, K. and Ito, Y. (2003) Effects of Metronidazole and Tinidazole Ointments on Models for Inflammatory Dermatitis in Mice. Arch. Dermatol. Res. 294, 544– 551, DOI: 10.1007/s00403-002-0381-4
  50
  Effects of metronidazole and tinidazole ointments on models for inflammatory dermatitis in mice
  Nishimuta, K.; Ito, Y.
  Archives of Dermatological Research (2003), 294 (12), 544-551CODEN: ADREDL; ISSN:0340-3696. (Springer-Verlag)
  We investigated the effects of 1-4% ointments of metronidazole and tinidazole (derivs. of nitroimidazole) on models of inflammatory dermatitis evoked by antigen, hapten and monoclonal anti-dinitrophenol (DNP) IgE antibody in mice. Metronidazole and tinidazole ointments (1) suppressed the late-phase reaction (LPR) of biphasic ear edema in mice sensitized with ovalbumin (OA), (2) suppressed trinitrochlorobenzene-induced inflammatory dermatitis, (3) suppressed the immediate phase reactions and LPR in mice passively sensitized with anti-DNP IgE mAb, and (4) enhanced vascular permeability and the no. of scratching reactions, presumably due to itching, in passively sensitized mice. These results strongly indicate that metronidazole and tinidazole 1-4% ointments possess antiinflammatory, immunosuppressive and anti-itching effects, and have the potential for clin. use in the treatment of human inflammatory skin diseases including atopic dermatitis in addn. to rosacea and acne vulgaris.
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51. 51
  Mendonca, C. O. and Griffiths, C. E. M. (2006) Clindamycin and Rifampicin Combination Therapy for Hidradenitis Suppurativa. Br. J. Dermatol. 154, 977– 978, DOI: 10.1111/j.1365-2133.2006.07155.x
  51
  Clindamycin and rifampicin combination therapy for hidradenitis suppurativa
  Mendonca, C. O.; Griffiths, C. E. M.
  British Journal of Dermatology (2006), 154 (5), 977-980CODEN: BJDEAZ; ISSN:0007-0963. (Blackwell Publishing Ltd.)
  Background: Hidradenitis suppurativa (HS) is a chronic inflammatory condition affecting apocrine gland-bearing areas of the skin. There is currently no satisfactory treatment. Objectives: To assess the efficacy of a 10-wk course of combination clindamycin 300 mg twice daily and rifampicin 300 mg twice daily in the treatment of HS. Methods: Patients who had received combination therapy with clindamycin and rifampicin for HS at one U.K. Dermatol. Center between the years 1998 and 2003 were identified from pharmacy records. Their records were analyzed retrospectively. Results: Fourteen patients with HS had received treatment with combination therapy. Eight of these patients achieved remission and a further two achieved remission when minocycline was substituted for clindamycin. Four patients were unable to tolerate therapy. Conclusions: This small retrospective study indicates that combination therapy with clindamycin and rifampicin may be effective for HS. However, there is a need for a placebo-controlled trial.
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52. 52
  Mela, M., Mancuso, A., and Burroughs, A. K. (2003) Review Article: Pruritus in Cholestatic and Other Liver Diseases. Aliment. Pharmacol. Ther. 17, 857– 870, DOI: 10.1046/j.1365-2036.2003.01458.x
  52
  Review article: pruritus in cholestatic and other liver diseases
  Mela, M.; Mancuso, A.; Burroughs, A. K.
  Alimentary Pharmacology and Therapeutics (2003), 17 (7), 857-870CODEN: APTHEN; ISSN:0269-2813. (Blackwell Publishing Ltd.)
  A review. Pruritus is often the most troublesome symptom in patients with chronic liver disease, particularly when cholestasis is a prominent feature. The exact pathogenesis is unknown, but empirical treatment such as cholestyramine, based on a liver-based origin of pruritus, has been used for many years. Recently, evidence for a central mechanism for pruritus has been obtained, and opioid antagonists have been tried clin. with some benefit, but their use is not widespread. In addn., the pruritus assocd. with intrahepatic cholestasis of pregnancy can now be alleviated in many cases by ursodeoxycholic acid. As it also improves fetal outcome, this should become 1st-line therapy. This article reviews the pathogenesis and therapy of pruritus, highlighting practical aspects to help patients with seemingly intractable pruritus.
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53. 53
  Sarici, G., Cinar, S., Armutcu, F., Altinyazar, C., Koca, R., and Tekin, N. S. (2010) Oxidative Stress in Acne Vulgaris. J. Eur. Acad. Dermatol. Venereol. 24, 763– 767, DOI: 10.1111/j.1468-3083.2009.03505.x
  53
  Oxidative stress in acne vulgaris
  Sarici, G.; Cinar, S.; Armutcu, F.; Altinyazar, C.; Koca, R.; Tekin, N. S.
  Journal of the European Academy of Dermatology and Venereology (2010), 24 (7), 763-767CODEN: JEAVEQ; ISSN:0926-9959. (Wiley-Blackwell)
  Background: Acne vulgaris is one of the common dermatol. diseases and its pathogenesis is multifactorial. In this study, we aimed to det. the effects of oxidative stress in acne vulgaris. Materials and methods: The study involved 32 patients with acne vulgaris in the patient group and 34 healthy adults in the control group. The parameters of oxidative stress such as catalase (CAT), superoxide dismutase (SOD), xanthine oxidase (XO), nitric oxide (NO) and malondialdehyde (MDA) in the venous blood of patients were measured spectrophotometrically. The values were compared with those of the control group. Results: The serum levels of MDA and XO activity in the patients with acne vulgaris were significantly higher than those of the controls. A significantly lower SOD and CAT activity was found in the patient group than in the control group. Although the patient group had higher serum levels of NO than the control group, the difference was not statistically significant. Conclusion: These results suggest that oxidative damage may play a role in the pathogenesis of acne; therefore, significant alterations may occur in the antioxidant defense system.
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54. 54
  Webster, G. F., Leyden, J. J., McGinley, K. J., and McArthur, W. P. (1982) Suppression of Polymorphonuclear Leukocyte Chemotactic Factor Production in Propionibacterium Acnes by Subminimal Inhibitory Concentrations of Tetracycline, Ampicillin, Minocycline, and Erythromycin. Antimicrob. Agents Chemother. 21, 770– 772, DOI: 10.1128/AAC.21.5.770
  54
  Suppression of polymorphonuclear leukocyte chemotactic factor production in Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocycline, and erythromycin
  Webster, G. F.; Leyden, J. J.; McGinley, K. J.; McArthur, W. P.
  Antimicrobial Agents and Chemotherapy (1982), 21 (5), 770-2CODEN: AMACCQ; ISSN:0066-4804.
  P. acnes Is the cause of inflammation in acne vulgaris and produces potent neutrophil chemoattractants. Different strains of P. acnes that were sensitive or resistant to ampicillin, erythromycin, minocycline, and tetracycline were grown in the presence of subminimal inhibitory concns. of the drugs, and their culture supernatants were assayed for neutrophil chemotactic activity. The presence of subminimal inhibitory concns. of ampicillin failed to affect chemotactic factor prodn. by any of the strains. Subminimal inhibitory concns. of tetracycline, minocycline, and erythromycin all produced decreased neutrophil chemotactic activity in P. acnes culture supernatants. This inhibition of chemotactic activity was most pronounced in strains of P. acnes which were susceptible to the drugs. The addn. of antibiotics at appropriate concns. to control supernatants failed to affect neutrophil migration. Thus, subminimal inhibitory concns. of antibiotics are capable of reducing the inflammatory capacity of P. acnes.
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55. 55
  Skidmore, R., Kovach, R., Walker, C., Thomas, J., Bradshaw, M., Leyden, J., Powala, C., and Ashley, R. (2003) Effects of Subantimicrobial-Dose Doxycycline in the Treatment of Moderate Acne. Arch. Dermatol. 139, 459– 464, DOI: 10.1001/archderm.139.4.459
  55
  Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne
  Skidmore, Robert; Kovach, Rodney; Walker, Clay; Thomas, John; Bradshaw, Mark; Leyden, James; Powala, Christopher; Ashley, Robert
  Archives of Dermatology (2003), 139 (4), 459-464CODEN: ARDEAC; ISSN:0003-987X. (American Medical Association)
  The aim of this study was to det. if treatment with subantimicrobial-dose (SD) doxycycline hyclate (20-mg tablets taken twice daily) improved clin. outcome, had any detectable effect on skin flora, led to overgrowth or colonization of skin by opportunistic pathogens, or resulted in an increase in antibiotic resistance by the surface skin microflora in patients with moderate acne compared with placebo. This was multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. The setting was two university-based clinics. Subjects were adults (N = 51) with moderate facial acne. Patients were randomized to receive SD doxycycline (Periostat; CollaGenex Pharmaceuticals Inc, Newtown, PA) or placebo twice daily for 6 mo. The main efficacy outcomes were changes from baseline in nos. of inflammatory, noninflammatory, and total lesions. Secondary outcome measures were changes from baseline of individual counts of papules, pustules, and nodules and global assessments of clin. improvement by patient and physician. Forty patients completed 6 mo of treatment. At 6 mo, the SD doxycycline group had a significantly greater percent redn. in the no. of comedones (P <.01), inflammatory and noninflammatory lesions combined (P <.01), and total inflammatory lesions (P <.05) than did the placebo group. They also had significantly greater improvement according to the clinician's global assessment (P =.03). There were no significant differences in microbial counts between groups and no evidence of change in antibiotic susceptibility or colonization by potential pathogens. The treatment was well tolerated. Twice-daily SD doxycycline treatment significantly reduced the no. of inflammatory and non-inflammatory lesions in patients with moderate facial acne, was well tolerated, had no detectable antimicrobial effect on the skin flora, and did not result in any increase in the no. of severity of resistant organisms.
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56. 56
  Strahl, H. and Hamoen, L. W. (2010) Membrane Potential Is Important for Bacterial Cell Division. Proc. Natl. Acad. Sci. U. S. A. 107, 12281– 12286, DOI: 10.1073/pnas.1005485107
  56
  Membrane potential is important for bacterial cell division
  Strahl, Henrik; Hamoen, Leendert W.
  Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (27), 12281-12286, S12281/1-S12281/12CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Many cell division-related proteins are located at specific positions in the bacterial cell, and this organized distribution of proteins requires energy. Here, the authors report that the proton motive force, or more specifically the (trans)membrane potential, is directly involved in protein localization. It emerged that the membrane potential modulates the distribution of several conserved cell division proteins such as MinD, FtsA, and the bacterial cytoskeletal protein MreB. The authors show for MinD that this is based on the membrane potential stimulated binding of its C-terminal amphipathic helix. This function of the membrane potential has implications for how these morphogenetic proteins work and provide an explanation for the effects obsd. with certain antimicrobial compds.
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57. 57
  Strahl, H., Burmann, F., and Hamoen, L. W. (2014) The Actin Homologue MreB Organizes the Bacterial Cell Membrane. Nat. Commun. 5, 3442, DOI: 10.1038/ncomms4442
  57
  The actin homologue MreB organizes the bacterial cell membrane
  Strahl Henrik; Burmann Frank; Hamoen Leendert W
  Nature communications (2014), 5 (), 3442 ISSN:.
  The eukaryotic cortical actin cytoskeleton creates specific lipid domains, including lipid rafts, which determine the distribution of many membrane proteins. Here we show that the bacterial actin homologue MreB displays a comparable activity. MreB forms membrane-associated filaments that coordinate bacterial cell wall synthesis. We noticed that the MreB cytoskeleton influences fluorescent staining of the cytoplasmic membrane. Detailed analyses combining an array of mutants, using specific lipid staining techniques and spectroscopic methods, revealed that MreB filaments create specific membrane regions with increased fluidity (RIFs). Interference with these fluid lipid domains (RIFs) perturbs overall lipid homeostasis and affects membrane protein localization. The influence of MreB on membrane organization and fluidity may explain why the active movement of MreB stimulates membrane protein diffusion. These novel MreB activities add additional complexity to bacterial cell membrane organization and have implications for many membrane-associated processes.
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58. 58
  Wenzel, M., Chiriac, A. I., Otto, A., Zweytick, D., May, C., Schumacher, C., Gust, R., Albada, H. B., Penkova, M., Krämer, U., Erdmann, R., Metzler-Nolte, N., Straus, S. K., Bremer, E., Becher, D., Brötz-Oesterhelt, H., Sahl, H.-G., and Bandow, J. E. (2014) Small Cationic Antimicrobial Peptides Delocalize Peripheral Membrane Proteins. Proc. Natl. Acad. Sci. U. S. A. 111, E1409– 18, DOI: 10.1073/pnas.1319900111
  58
  Small cationic antimicrobial peptides delocalize peripheral membrane proteins
  Wenzel, Michaela; Chiriac, Alina Iulia; Otto, Andreas; Zweytick, Dagmar; May, Caroline; Schumacher, Catherine; Gust, Ronald; Albada, H. Bauke; Penkova, Maya; Kraemer, Ute; Erdmann, Ralf; Metzler-Nolte, Nils; Straus, Suzana K.; Bremer, Erhard; Becher, Doerte; Broetz-Oesterhelt, Heike; Sahl, Hans-Georg; Bandow, Julia Elisabeth
  Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (14), E1409-E1418CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Short antimicrobial peptides rich in arginine (R) and tryptophan (W) interact with membranes. To learn how this interaction leads to bacterial death, the authors characterized the effects of the minimal pharmacophore RWRWRW-NH2. A ruthenium-substituted deriv. of this peptide localized to the membrane in vivo, and the peptide also integrated readily into mixed phospholipid bilayers that resemble Gram-pos. membranes. Proteome and Western blot analyses showed that integration of the peptide caused delocalization of peripheral membrane proteins essential for respiration and cell-wall biosynthesis, limiting cellular energy and undermining cell-wall integrity. This delocalization phenomenon also was obsd. with the cyclic peptide gramicidin S, indicating the generality of the mechanism. Exogenous glutamate increases tolerance to the peptide, indicating that osmotic destabilization also contributes to antibacterial efficacy. Bacillus subtilis responds to peptide stress by releasing osmoprotective amino acids, in part via mechanosensitive channels. This response is triggered by membrane-targeting bacteriolytic peptides of different structural classes as well as by hypoosmotic conditions.
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59. 59
  Pogliano, J., Pogliano, N., and Silverman, J. A. (2012) Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell Division Proteins. J. Bacteriol. 194, 4494– 4504, DOI: 10.1128/JB.00011-12
  59
  Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins
  Pogliano, Joe; Pogliano, Nicolas; Silverman, Jared A.
  Journal of Bacteriology (2012), 194 (17), 4494-4504CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
  Daptomycin is a lipopeptide antibiotic used clin. for the treatment of certain types of Gram-pos. infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Details of the mechanism of action of daptomycin continue to be elucidated, particularly the question of whether daptomycin acts on the cell membrane, the cell wall, or both. Here, we use fluorescence microscopy to directly visualize the interaction of daptomycin with the model Gram-pos. bacterium Bacillus subtilis. We show that the first observable cellular effects are the formation of membrane distortions (patches of membrane) that precede cell death by more than 30 min. Membrane patches are able to recruit the essential cell division protein DivIVA. Recruitment of DivIVA correlates with membrane defects and changes in cell morphol., suggesting a localized alteration in the activity of enzymes involved in cell wall synthesis that could account for previously described effects of daptomycin on cell wall morphol. and septation. Membrane defects colocalize with fluorescently labeled daptomycin, DivIVA, and fluorescent reporters of peptidoglycan biogenesis (Bocillin FL and BODIPY FL-vancomycin), suggesting that daptomycin plays a direct role in these events. Our results support a mechanism for daptomycin with a primary effect on cell membranes that in turn redirects the localization of proteins involved in cell division and cell wall synthesis, causing dramatic cell wall and membrane defects, which may ultimately lead to a breach in the cell membrane and cell death. These results help resolve the long-standing questions regarding the mechanism of action of this important class of antibiotics.
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60. 60
  Morgera, F., Antcheva, N., Pacor, S., Quaroni, L., Berti, F., Vaccari, L., and Tossi, A. (2008) Structuring and Interactions of Human Beta-Defensins 2 and 3 with Model Membranes. J. Pept. Sci. 14, 518– 523, DOI: 10.1002/psc.981
  60
  Structuring and interactions of human β-defensins 2 and 3 with model membranes
  Morgera, Francesca; Antcheva, Nikolinka; Pacor, Sabrina; Quaroni, Luca; Berti, Federico; Vaccari, Lisa; Tossi, Alessandro
  Journal of Peptide Science (2008), 14 (4), 518-523CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
  β-Defensins play an important role in both innate and adaptive immunity, displaying a direct anti-microbial activity against a wide variety of micro-organisms as well as interesting immuno-modulatory effects on host cells. Interaction with biol. membranes appears to be a central theme in modulating these activities, leading to different consequences such as membrane lysis, translocation into the cytoplasm or transfer to a receptor. We have investigated the structuring of human β-defensins (hBD2 and hBD3) and rationally designed variants, in relation to their interactions with real and model membranes. Biophys. methods, such as CD (CD), transmission or reflection IR and dye release were used to probe their structure/activity in the presence of model membranes, while fluorimetric and flow cytometric assays were used to investigate the effects on prokaryotic cells. Our results indicate that structural features, such as the helical N-terminal domains and oligomerization at the membrane surface, may modulate the efficiency of membrane insertion and selectivity for microbial or host-cell membranes. We propose that both peptides interact with membranes as extended β-sheet platforms that present amphipathic helixes for insertion into the lipid bilayer.
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61. 61
  Sass, V., Schneider, T., Wilmes, M., Körner, C., Tossi, A., Novikova, N., Shamova, O., and Sahl, H. G. (2010) Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci. Infect. Immun. 78, 2793– 2800, DOI: 10.1128/IAI.00688-09
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  Human β-defensin 3 inhibits cell wall biosynthesis in staphylococci
  Sass, Vera; Schneider, Tanja; Wilmes, Miriam; Koerner, Christian; Tossi, Alessandro; Novikova, Natalia; Shamova, Olga; Sahl, Hans-Georg
  Infection and Immunity (2010), 78 (6), 2793-2800CODEN: INFIBR; ISSN:0019-9567. (American Society for Microbiology)
  Human β-defensin 3 (hBD3) is a highly charged (+11) cationic host defense peptide, produced by epithelial cells and neutrophils. HBD3 retains antimicrobial activity against a broad range of pathogens, including multiresistant Staphylococcus aureus, even under high-salt conditions. Whereas antimicrobial host defense peptides are assumed to act by permeabilizing cell membranes, the transcriptional response pattern of hBD3-treated staphylococcal cells resembled that of vancomycin-treated cells and suggested that inhibition of cell wall biosynthesis is a major component of the killing process. HBD3-treated cells, inspected by transmission electron microscopy, showed localized protrusions of cytoplasmic contents, and anal. of the intracellular pool of nucleotide-activated cell wall precursors demonstrated accumulation of the final sol. precursor, UDP-MurNAc-pentapeptide. Accumulation is typically induced by antibiotics that inhibit membrane-bound steps of cell wall biosynthesis and also demonstrates that hBD3 does not impair the biosynthetic capacity of cells and does not cause gross leakage of small cytoplasmic compds. In in vitro assays of individual membrane-assocd. cell wall biosynthesis reactions (MraY, MurG, FemX, and penicillin-binding protein 2 [PBP2]), hBD3 inhibited those enzymes which use the bactoprenol-bound cell wall building block lipid II as a substrate; quant. anal. suggested that hBD3 may stoichiometrically bind to lipid II. We report that binding of hBD3 to defined, lipid II-rich sites of cell wall biosynthesis may lead to perturbation of the biosynthesis machinery, resulting in localized lesions in the cell wall as demonstrated by electron microscopy. The lesions may then allow for osmotic rupture of cells when defensins are tested under low-salt conditions.
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62. 62
  Kandaswamy, K., Liew, T. H., Wang, C. Y., Huston-Warren, E., Meyer-Hoffert, U., Hultenby, K., Schröder, J. M., Caparon, M. G., Normark, S., Henriques-Normark, B., Hultgren, S. J., and Kline, K. A. (2013) Focal Targeting by Human β-Defensin 2 Disrupts Localized Virulence Factor Assembly Sites in Enterococcus Faecalis. Proc. Natl. Acad. Sci. U. S. A. 110, 20230– 20235, DOI: 10.1073/pnas.1319066110
  62
  Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis
  Kandaswamy, Kumaravel; Liew, Tze Horng; Wang, Charles Y.; Huston-Warren, Emily; Meyer-Hoffert, Ulf; Hultenby, Kjell; Schroder, Jens M.; Caparon, Michael G.; Normark, Staffan; Henriques-Normark, Birgitta; Hultgren, Scott J.; Kline, Kimberly A.
  Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (50), 20230-20235,S20230/1-S20230/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Virulence factor secretion and assembly occurs at spatially restricted foci in some Gram-pos. bacteria. Given the essentiality of the general secretion pathway in bacteria and the contribution of virulence factors to disease progression, the foci that coordinate these processes are attractive antimicrobial targets. In this study, the authors show in Enterococcus faecalis that SecA and sortase A, required for the attachment of virulence factors to the cell wall, localize to discrete domains near the septum or nascent septal site as the bacteria proceed through the cell cycle. They also demonstrate that cationic human β-defensins interact with E. faecalis at discrete septal foci, and this exposure disrupts sites of localized secretion and sorting. Modification of anionic lipids by multiple peptide resistance factor, a protein that confers antimicrobial peptide resistance by electrostatic repulsion, renders E. faecalis more resistant to killing by defensins and less susceptible to focal targeting by the cationic antimicrobial peptides. These data suggest a paradigm in which focal targeting by antimicrobial peptides is linked to their killing efficiency and to disruption of virulence factor assembly.
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63. 63
  Kwakman, P. H. S., Krijgsveld, J., de Boer, L., Nguyen, L. T., Boszhard, L., Vreede, J., Dekker, H. L., Speijer, D., Drijfhout, J. W., te Velde, A. A., Crielaard, W., Vogel, H. J., Vandenbroucke-Grauls, C. M. J. E., and Zaat, S. A. J. (2011) Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements. J. Biol. Chem. 286, 43506– 43514, DOI: 10.1074/jbc.M111.248641
  63
  Native thrombocidin-1 and unfolded thrombocidin-1 exert antimicrobial activity via distinct structural elements
  Kwakman, Paulus H. S.; Krijgsveld, Jeroen; de Boer, Leonie; Nguyen, Leonard T.; Boszhard, Laura; Vreede, Jocelyne; Dekker, Henk L.; Speijer, Dave; Drijfhout, Jan W.; te Velde, Anje A.; Crielaard, Wim; Vogel, Hans J.; Vandenbroucke-Grauls, Christina M. J. E.; Zaat, Sebastian A. J.
  Journal of Biological Chemistry (2011), 286 (50), 43506-43514, S43506/1-S43506/2CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Chemokines (chemotactic cytokines) can have direct antimicrobial activity, which is apparently related to the presence of a distinct pos. charged patch on the surface. However, chemokines can retain antimicrobial activity upon linearization despite the loss of their pos. patch, thus questioning the importance of this patch for activity. Thrombocidin-1 (TC-1) is a microbicidal protein isolated from human blood platelets. TC-1 only differs from the chemokine NAP-2/CXCL7 by a two-amino acid C-terminal deletion, but this truncation is crucial for antimicrobial activity. The authors assessed the structure-activity relationship for antimicrobial activity of TC-1. Redn. of the charge of the TC-1-pos. patch by replacing lysine 17 with alanine reduced the activity against bacteria and almost abolished activity against the yeast Candida albicans. Conversely, augmentation of the pos. patch by increasing charge d. or size resulted in a 2-3-fold increased activity against Staphylococcus aureus, Escherichia coli, and Bacillus subtilis but did not substantially affect activity against C. albicans. Redn. of TC-1 resulted in loss of the folded conformation, but this disruption of the pos. patch did not affect antimicrobial activity. Using overlapping 15-mer synthetic peptides, we demonstrate peptides corresponding to the N-terminal part of TC-1 to have similar antimicrobial activity as intact TC-1. Although we demonstrate that the pos. patch is essential for activity of folded TC-1, unfolded TC-1 retained antimicrobial activity despite the absence of a pos. patch. This activity is probably exerted by a linear peptide stretch in the N-terminal part of the mol. It is concluded that intact TC-1 and unfolded TC-1 exert antimicrobial activity via distinct structural elements.
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64. 64
  Omardien, S., Drijfhout, J. W., Vaz, F. M., Wenzel, M., Hamoen, L. W., Zaat, S. A. J., and Brul, S. (2018) Bactericidal Activity of Amphipathic Cationic Antimicrobial Peptides Involves Altering the Membrane Fluidity When Interacting with the Phospholipid Bilayer. Biochim. Biophys. Acta, Biomembr. 1860, 2404, DOI: 10.1016/j.bbamem.2018.06.004
  64
  Bactericidal activity of amphipathic cationic antimicrobial peptides involves altering the membrane fluidity when interacting with the phospholipid bilayer
  Omardien, Soraya; Drijfhout, Jan W.; Vaz, Frederic M.; Wenzel, Michaela; Hamoen, Leendert W.; Zaat, Sebastian A. J.; Brul, Stanley
  Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (11), 2404-2415CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Amphipathic cationic antimicrobial peptides (AMPs) TC19 and TC84, derived from the major AMPs of human blood platelets, thrombocidins, and Bactericidal Peptide 2 (BP2), a synthetic designer peptide showed to perturb the membrane of Bacillus subtilis. We aimed to det. the means by which the three AMPs cause membrane perturbation in vivo using B. subtilis and to evaluate whether the membrane alterations are dependent on the phospholipid compn. of the membrane. Physiol. anal. was employed using Alexa Fluor 488 labeled TC84, various fluorescence dyes, fluorescent microscopy techniques and structured illumination microscopy. TC19, TC84 and BP2 created extensive fluidity domains in the membrane that are permeable, thus facilitating the entering of the peptides and the leakage of the cytosol. The direct interaction of the peptides with the bilayer create the fluid domains. The changes caused in the packing of the phospholipids lead to the delocalization of membrane bound proteins, thus contributing to the cell's destruction. The changes made to the membrane appeared to be not dependent on the compn. of the phospholipid bilayer. The distortion caused to the fluidity of the membrane by the AMPs is sufficient to facilitate the entering of the peptides and leakage of the cytosol. Here we show in vivo that cationic AMPs cause "membrane leaks" at the site of membrane insertion by altering the organization and fluidity of the membrane. Our findings thus contribute to the understanding of the membrane perturbation characteristic of cationic AMPs.
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65. 65
  Omardien, S., Drijfhout, J. W., van Veen, H., Schachtschabel, S., Riool, M., Hamoen, L. W., Brul, S., and Zaat, S. A. J. (2018) Synthetic Antimicrobial Peptides Delocalize Membrane Bound Proteins Thereby Inducing a Cell Envelope Stress Response. Biochim. Biophys. Acta, Biomembr. 1860, 2416– 2427, DOI: 10.1016/j.bbamem.2018.06.005
  65
  Synthetic antimicrobial peptides delocalize membrane bound proteins thereby inducing a cell envelope stress response
  Omardien, Soraya; Drijfhout, Jan W.; van Veen, Henk; Schachtschabel, Soraya; Riool, Martijn; Hamoen, Leendert W.; Brul, Stanley; Zaat, Sebastian A. J.
  Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (11), 2416-2427CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Three amphipathic cationic antimicrobial peptides (AMPs) were characterized by detg. their effect on Gram-pos. bacteria using Bacillus subtilis strain 168 as a model organism. These peptides were TC19 and TC84, derivs. of thrombocidin-1 (TC-1), the major AMPs of human blood platelets, and Bactericidal Peptide 2 (BP2), a synthetic designer peptide based on human bactericidal permeability increasing protein (BPI). To elucidate the possible mode of action of the AMPs we performed a transcriptomic anal. using microarrays. Physiol. analyses were performed using transmission electron microscopy (TEM), fluorescence microscopy and various B. subtilis mutants that produce essential membrane bound proteins fused to green fluorescent protein (GFP). The transcriptome anal. showed that the AMPs induced a cell envelope stress response (cell membrane and cell wall). The cell membrane stress response was confirmed with the physiol. observations that TC19, TC84 and BP2 perturb the membrane of B. subtilis. Using B. subtilis mutants, we established that the cell wall stress response is due to the delocalization of essential membrane bound proteins involved in cell wall synthesis. Other essential membrane proteins, involved in cell membrane synthesis and metab., were also delocalized due to alterations caused by the AMPs. We showed that peptides TC19, TC84 and BP2 perturb the membrane causing essential proteins to delocalize, thus preventing the possible repair of the cell envelope after the initial interference with the membrane. These AMPs show potential for eventual clin. application against Gram-pos. bacterial cells and merit further application-oriented investigation.
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66. 66
  Omardien, S., Drijfhout, J. W., Zaat, S. A., and Brul, S. (2018) Cationic Amphipathic Antimicrobial Peptides Perturb the Inner Membrane of Germinated Spores Thus Inhibiting Their Outgrowth. Front. Microbiol. 9, 2277, DOI: 10.3389/fmicb.2018.02277
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  Cationic Amphipathic Antimicrobial Peptides Perturb the Inner Membrane of Germinated Spores Thus Inhibiting Their Outgrowth
  Omardien Soraya; Brul Stanley; Drijfhout Jan Wouter; Zaat Sebastian A
  Frontiers in microbiology (2018), 9 (), 2277 ISSN:1664-302X.
  The mode of action of four cationic amphipathic antimicrobial peptides (AMPs) was evaluated against the non-pathogenic, Gram-positive, spore-forming bacterium, Bacillus subtilis. The AMPs were TC19, TC84, BP2, and the lantibiotic Nisin A. TC19 and TC84 were derived from the human thrombocidin-1. Bactericidal peptide 2 (BP2) was derived from the human bactericidal permeability increasing protein (BPI). We employed structured illumination microscopy (SIM), fluorescence microscopy, Alexa 488-labeled TC84, B. subtilis mutants producing proteins fused to the green fluorescent protein (GFP) and single-cell live imaging to determine the effects of the peptides against spores. TC19, TC84, BP2, and Nisin A showed to be bactericidal against germinated spores by perturbing the inner membrane, thus preventing outgrowth to vegetative cells. Single cell live imaging showed that the AMPs do not affect the germination process, but the burst time and subsequent generation time of vegetative cells. Alexa 488-labeled TC84 suggested that the TC84 might be binding to the dormant spore-coat. Therefore, dormant spores were also pre-coated with the AMPs and cultured on AMP-free culture medium during single-cell live imaging. Pre-coating of the spores with TC19, TC84, and BP2 had no effect on the germination process, and variably affected the burst time and generation time. However, the percentage of spores that burst and grew out into vegetative cells was drastically lower when pre-coated with Nisin A, suggesting a novel application potential of this lantibiotic peptide against spores. Our findings contribute to the understanding of AMPs and show the potential of AMPs as eventual therapeutic agents against spore-forming bacteria.
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67. 67
  Gray, D. A. and Wenzel, M. (2020) More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin. Antibiotics (Basel, Switz.) 9, 17, DOI: 10.3390/antibiotics9010017
  67
  More than a pore: a current perspective on the in vivo mode of action of the lipopeptide antibiotic daptomycin
  Gray, Declan Alan; Wenzel, Michaela
  Antibiotics (Basel, Switzerland) (2020), 9 (1), 17CODEN: ABSNC4; ISSN:2079-6382. (MDPI AG)
  Daptomycin is a cyclic lipopeptide antibiotic, which was discovered in 1987 and entered the market in 2003. To date, it serves as last resort antibiotic to treat complicated skin infections, bacteremia, and right-sided endocarditis caused by Gram-pos. pathogens, most prominently methicillin-resistant Staphylococcus aureus. Daptomycin was the last representative of a novel antibiotic class that was introduced to the clinic. It is also one of the few membrane-active compds. that can be applied systemically. While membrane-active antibiotics have long been limited to topical applications and were generally excluded from systemic drug development, they promise slower resistance development than many classical drugs that target single proteins. The success of daptomycin together with the emergence of more and more multi-resistant superbugs attracted renewed interest in this compd. class. Studying daptomycin as a pioneering systemic membrane-active compd. might help to pave the way for future membrane-targeting antibiotics. However, more than 30 years after its discovery, the exact mechanism of action of daptomycin is still debated. In particular, there is a prominent discrepancy between in vivo and in vitro studies. In this review, we discuss the current knowledge on the mechanism of daptomycin against Gram-pos. bacteria and try to offer explanations for these conflicting observations.
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68. 68
  Scheinpflug, K., Wenzel, M., Krylova, O., Bandow, E. J., Dathe, M., and Strahl, H. (2017) Antimicrobial Peptide CWFW Kills by Combining Lipid Phase Separation with Autolysis. Sci. Rep. 7, 44332, DOI: 10.1038/srep44332
  68
  Antimicrobial peptide cWFW kills by combining lipid phase separation with autolysis
  Scheinpflug Kathi; Krylova Oxana; Dathe Margitta; Wenzel Michaela; Bandow Julia E; Strahl Henrik
  Scientific reports (2017), 7 (), 44332 ISSN:.
  The synthetic cyclic hexapeptide cWFW (cyclo(RRRWFW)) has a rapid bactericidal activity against both Gram-positive and Gram-negative bacteria. Its detailed mode of action has, however, remained elusive. In contrast to most antimicrobial peptides, cWFW neither permeabilizes the membrane nor translocates to the cytoplasm. Using a combination of proteome analysis, fluorescence microscopy, and membrane analysis we show that cWFW instead triggers a rapid reduction of membrane fluidity both in live Bacillus subtilis cells and in model membranes. This immediate activity is accompanied by formation of distinct membrane domains which differ in local membrane fluidity, and which severely disrupts membrane protein organisation by segregating peripheral and integral proteins into domains of different rigidity. These major membrane disturbances cause specific inhibition of cell wall synthesis, and trigger autolysis. This novel antibacterial mode of action holds a low risk to induce bacterial resistance, and provides valuable information for the design of new synthetic antimicrobial peptides.
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69. 69
  Saeloh, D., Tipmanee, V., Jim, K. K., Dekker, M. P., Bitter, W., Voravuthikunchai, S. P., Wenzel, M., and Hamoen, L. W. (2018) The Novel Antibiotic Rhodomyrtone Traps Membrane Proteins in Vesicles with Increased Fluidity. PLoS Pathog. 14, e1006876 DOI: 10.1371/journal.ppat.1006876
  69
  The novel antibiotic rhodomyrtone traps membrane proteins in vesicles with increased fluidity
  Saeloh, Dennapa; Tipmanee, Varomyalin; Jim, Kin Ki; Dekker, Marien P.; Bitter, Wilbert; Voravuthikunchai, Supayang P.; Wenzel, Michaela; Hamoen, Leendert W.
  PLoS Pathogens (2018), 14 (2), e1006876/1-e1006876/35CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  The acylphloroglucinol rhodomyrtone is a promising new antibiotic isolated from the rose myrtle Rhodomyrtus tomentosa, a plant used in Asian traditional medicine. While many studies have demonstrated its antibacterial potential in a variety of clin. applications, very little is known about the mechanism of action of rhodomyrtone. Preceding studies have been focused on intracellular targets, but no specific intracellular protein could be confirmed as main target. Using live cell, high-resoln., and electron microscopy we demonstrate that rhodomyrtone causes large membrane invaginations with a dramatic increase in fluidity, which attract a broad range of membrane proteins. Invaginations then form intracellular vesicles, thereby trapping these proteins. Aberrant protein localization impairs several cellular functions, including the respiratory chain and the ATP synthase complex. Being uncharged and devoid of a particular amphipathic structure, rhodomyrtone did not seem to be a typical membrane-inserting mol. In fact, mol. dynamics simulations showed that instead of inserting into the bilayer, rhodomyrtone transiently binds to phospholipid head groups and causes distortion of lipid packing, providing explanations for membrane fluidization and induction of membrane curvature. Both its transient binding mode and its ability to form protein- trapping membrane vesicles are unique, making it an attractive new antibiotic candidate with a novel mechanism of action.
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70. 70
  Zhanel, G. G., Schweizer, F., and Karlowsky, J. A. (2012) Oritavancin: Mechanism of Action. Clin. Infect. Dis. 54, S214– S219, DOI: 10.1093/cid/cir920
  70
  Oritavancin: Mechanism of Action
  Zhanel, George G.; Schweizer, Frank; Karlowsky, James A.
  Clinical Infectious Diseases (2012), 54 (Suppl. 3), S214-S219CODEN: CIDIEL; ISSN:1058-4838. (Oxford University Press)
  A review. Oritavancin is a semisynthetic lipoglycopeptide analog of vancomycin that contains the heptapeptide core common to all glycopeptides. It differs from vancomycin by the presence of a hydrophobic N-4-(4-chlorophenyl)benzyl (also referred to as 4'-chlorobiphenylmethyl) substituent on the disaccharide sugar, the addn. of a 4-epi-vancosamine monosaccharide to the amino acid residue in ring 6, and the replacement of the vancosamine moiety by 4-epi-vancosamine. One mechanism of action of oritavancin is inhibition of transglycosylation (important in peptidoglycan synthesis) by binding to -alanyl-alanine stem termini in Gram-pos. bacteria. The inhibition of peptidoglycan synthesis via inhibition of transglycosylation is common to all glycopeptides (vancomycin) and lipoglycopeptides. Secondary binding of oritavancin to the pentaglycyl (Asp/Asn) bridging segment in peptidoglycan also occurs, which distinguishes it from vancomycin and contributes to oritavancin's activity vs. vancomycin-resistant organisms. The presence of the hydrophobic 4'-chlorobiphenylmethyl group allows for interaction and disruption of the cell membrane, resulting in depolarization, permeabilization, and concn.-dependent, rapid cell death. This mechanism is shared with telavancin but not vancomycin and results in activity against daptomycin-nonsusceptible organisms. In conclusion, oritavancin's mechanism of action involves at least 3 known mechanisms: inhibition of transglycosylation, inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin's multiple mechanisms of action confer activity against vancomycin-susceptible and -resistant organisms, as well as rapid, concn.-dependent killing vs. actively growing, stationary phase, and biofilm-producing Gram-pos. bacteria.
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71. 71
  Higgins, D. L., Chang, R., Debabov, D. V., Leung, J., Wu, T., Krause, K. M., Sandvik, E., Hubbard, J. M., Kaniga, K., Schmidt, D. E., Gao, Q., Cass, R. T., Karr, D. E., Benton, B. M., and Humphrey, P. P. (2005) Telavancin, a Multifunctional Lipoglycopeptide, Disrupts Both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistan Staphylococcus Aureus. Antimicrob. Agents Chemother. 49, 1127– 1134, DOI: 10.1128/AAC.49.3.1127-1134.2005
  71
  Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus
  Higgins, Deborah L.; Chang, Ray; Debabov, Dmitri V.; Leung, Joey; Wu, Terry; Krause, Kevin M.; Sandvik, Erik; Hubbard, Jeffrey M.; Kaniga, Kone; Schmidt, Donald E., Jr.; Gao, Qiufeng; Cass, Robert T.; Karr, Dane E.; Benton, Bret M.; Humphrey, Patrick P.
  Antimicrobial Agents and Chemotherapy (2005), 49 (3), 1127-1134CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The emergence and spread of multidrug-resistant Gram-pos. bacteria represent a serious clin. problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clin. relevant Gram-pos. pathogens. Here, the authors demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As obsd. with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concn.-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K+. The timing of these changes correlated with rapid, concn.-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were obsd. with the bacterial cell wall and cell membrane relative to vancomycin. It is suggested that this multifunctional mechanism of action confers advantageous antibacterial properties.
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72. 72
  Corti, A. and Cassani, G. (1985) Synthesis and Characterization of D-Alanyl-D-Alanine-Agarose. Appl. Biochem. Biotechnol. 11, 101– 109, DOI: 10.1007/BF02798542
  72
  Synthesis and characterization of D-alanyl-D-alanine-agarose. A new bioselective adsorbent for affinity chromatography of glycopeptide antibiotics
  Corti, Angelo; Cassani, Giovanni
  Applied Biochemistry and Biotechnology (1985), 11 (2), 101-9CODEN: ABIBDL; ISSN:0273-2289.
  A new affinity absorbent, using D-alanyl-D-alanine [923-16-0] as ligand, has been prepd. The dipeptide immobilized on Activated CH-Sepharose 4B [D-Ala-D-Ala-agarose (I) [95077-98-8]] bioselectively binds the glycopeptide antibiotics teicoplanin [61036-62-2], vancomycin [1404-90-6], ristocetin A [11021-66-2] (vancomycin-like group of antibiotics) while it does not bind other antibiotics equally active on cell wall biosynthesis but with target sites other than D-ala-D-ala. Teicoplanin, vancomycin, and ristocetin A have similar binding characteristics for the immobilized dipeptide, as indicated by equil. binding expts. The affinity consts. of the 3 antibiotics for I is of the same order of magnitude (105 L mol-1) and the no. of effective binding sites is similar for each antibiotic (6-7 μEq/mL gel). The adsorption is biospecific as no binding has been obsd. to immobilized L-alanyl-L-alanine. I was successfully used to purify teicoplanin from mixts. of different complexity and for concomitant extn. and purifn. from fermn. liquors by both batch adsorption and column chromatog. The antibiotic can be recovered from the resin in high yields by elution at pH 11.
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73. 73
  Cheng, M., Ziora, Z. M., Hansford, K. A., Blaskovich, M. A., Butler, M. S., and Cooper, M. A. (2014) Anti-Cooperative Ligand Binding and Dimerisation in the Glycopeptide Antibiotic Dalbavancin. Org. Biomol. Chem. 12, 2568– 2575, DOI: 10.1039/C3OB42428F
  73
  Anti-cooperative ligand binding and dimerisation in the glycopeptide antibiotic dalbavancin
  Cheng, Mu; Ziora, Zyta M.; Hansford, Karl A.; Blaskovich, Mark A.; Butler, Mark S.; Cooper, Matthew A.
  Organic & Biomolecular Chemistry (2014), 12 (16), 2568-2575CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  Dalbavancin, a semi-synthetic glycopeptide with enhanced antibiotic activity compared to vancomycin and teicoplanin, binds to the C-terminal lysyl-D-alanyl-D-alanine subunit of Lipid II, inhibiting peptidoglycan biosynthesis. In this study, micro-calorimetry (ITC) and electrospray ionization (ESI)-MS have been used to investigate the relationship between oligomerization of dalbavancin and binding of a Lipid II peptide mimic, diacetyl-Lys-D-Ala-D-Ala (Ac2-Kaa). Dalbavancin dimerized strongly in an anti-cooperative manner with ligand-binding, as was the case for ristocetin A, but not for vancomycin and teicoplanin. Dalbavancin and ristocetin A both adopt an 'closed' conformation upon ligand binding, suggesting anti-cooperative dimerization with ligand-binding may be a general feature of dalbavancin/ristocetin A-like glycopeptides. Understanding these effects may provide insight into design of novel dalbavancin derivs. with cooperative ligand-binding and dimerization characteristics that could enhance antibiotic activity.
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74. 74
  Wenzel, M., Kohl, B., Münch, D., Raatschen, N., Albada, H. B., Hamoen, L., Metzler-Nolte, N., Sahl, H. G., and Bandow, J. E. (2012) Proteomic Response of Bacillus Subtilis to Lantibiotics Reflects Differences in Interaction with the Cytoplasmic Membrane. Antimicrob. Agents Chemother. 56, 5749– 5757, DOI: 10.1128/AAC.01380-12
  74
  Proteomic response of Bacillus subtilis to lantibiotics reflects differences in interaction with the cytoplasmic membrane
  Wenzel, Michaela; Kohl, Bastian; Muench, Daniela; Raatschen, Nadja; Albada, H. Bauke; Hamoen, Leendert; Metzler-Nolte, Nils; Sahl, Hans-Georg; Bandow, Julia E.
  Antimicrobial Agents and Chemotherapy (2012), 56 (11), 5749-5757CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  Mersacidin, gallidermin, and nisin are lantibiotics, antimicrobial peptides contg. lanthionine. They show potent antibacterial activity. All three interfere with cell wall biosynthesis by binding lipid II, but they display different levels of interaction with the cytoplasmic membrane. On one end of the spectrum, mersacidin interferes with cell wall biosynthesis by binding lipid II without integrating into bacterial membranes. On the other end of the spectrum, nisin readily integrates into membranes, where it forms large pores. It destroys the membrane potential and causes leakage of nutrients and ions. Gallidermin, in an intermediate position, also readily integrates into membranes. However, pore formation occurs only in some bacteria and depends on membrane compn. The authors studied the impact of nisin, gallidermin, and mersacidin on cell wall integrity, membrane pore formation, and membrane depolarization in Bacillus subtilis. The impact of the lantibiotics on the cell envelope was correlated to the proteomic response they elicit in B. subtilis. By drawing on a proteomic response library, including other envelope-targeting antibiotics such as bacitracin, vancomycin, gramicidin S, or valinomycin, YtrE could be identified as the most reliable marker protein for interfering with membrane-bound steps of cell wall biosynthesis. NadE and PspA were identified as markers for antibiotics interacting with the cytoplasmic membrane.
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75. 75
  Bonelli, R. R., Schneider, T., Sahl, H.-G., and Wiedemann, I. (2006) Insights into in Vivo Activities of Lantibiotics from Gallidermin and Epidermin Mode-of-Action Studies. Antimicrob. Agents Chemother. 50, 1449– 1457, DOI: 10.1128/AAC.50.4.1449-1457.2006
  75
  Insights into in vivo activities of lantibiotics from gallidermin and epidermin mode-of-action studies
  Bonelli, Raquel Regina; Schneider, Tanja; Sahl, Hans-Georg; Wiedemann, Imke
  Antimicrobial Agents and Chemotherapy (2006), 50 (4), 1449-1457CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The activity of lanthionine-contg. peptide antibiotics (lantibiotics) is based on different killing mechanisms which may be combined in one mol. The prototype lantibiotic nisin inhibits peptidoglycan synthesis and forms pores through specific interaction with the cell wall precursor lipid II. Gallidermin and epidermin possess the same putative lipid II binding motif as nisin; however, both peptides are considerably shorter (22 amino acids, compared to 34 in nisin). We demonstrate that in model membranes, lipid II-mediated pore formation by gallidermin depends on membrane thickness. With intact cells, pore formation was less pronounced than for nisin and occurred only in some strains. In Lactococcus lactis subsp. cremoris HP, gallidermin was not able to release K+, and a mutant peptide, [A12L]gallidermin, in which the ability to form pores was disrupted, was as potent as wild-type gallidermin, indicating that pore formation does not contribute to killing. In contrast, nisin rapidly formed pores in the L. lactis strain; however, it was approx. 10-fold less effective in killing. The superior activity of gallidermin in a cell wall biosynthesis assay may help to explain this high potency. Generally, it appears that the multiple activities of lantibiotics combine differently for individual target strains.
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76. 76
  Brötz, H., Bierbaum, G., Leopold, K., Reynolds, P. E., and Sahl, H. G. (1998) The Lantibiotic Mersacidin Inhibits Peptidoglycan Synthesis by Targeting Lipid II. Antimicrob. Agents Chemother. 42, 154– 160, DOI: 10.1128/AAC.42.1.154
  76
  The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting lipid II
  Brotz, Heike; Bierbaum, Gabriele; Leopold, Klaus; Reynolds, Peter E.; Sahl, Hans-Georg
  Antimicrobial Agents and Chemotherapy (1998), 42 (1), 154-160CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The lantibiotic mersacidin exerts its bactericidal action by inhibition of peptidoglycan biosynthesis. It interferes with the membrane-assocd. transglycosylation reaction; during this step the ultimate monomeric peptidoglycan precursor, undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-GlcNAc (lipid II) is converted into polymeric nascent peptidoglycan. In the present study we demonstrate that the mol. basis of this inhibition is the interaction of mersacidin with lipid II. The adsorption of [14C]mersacidin to growing cells, as well as to isolated membranes capable of in vitro peptidoglycan synthesis, was strictly dependent on the availability of lipid II, and antibiotic inhibitors of lipid II formation strongly interfered with this binding. Direct evidence for the interaction was provided by studies with isolated lipid II. [14C]mersacidin assocd. tightly with [14C]lipid II micelles; the complex was stable even in the presence of 1% sodium dodecyl sulfate. Furthermore, the addn. of isolated lipid II to the culture broth efficiently antagonized the bactericidal activity of mersacidin. In contrast to the glycopeptide antibiotics, complex formation does not involve the C-terminal D-alanyl-D-alanine moiety of the lipid intermediate. Thus, the interaction of mersacidin with lipid II apparently occurs via a binding site which is not targeted by any antibiotic currently in use.
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77. 77
  Paris, J.-B., Seyer, D., Jouenne, T., and Thébault, P. (2017) Elaboration of Antibacterial Plastic Surfaces by a Combination of Antiadhesive and Biocidal Coatings of Natural Products. Colloids Surf., B 156, 186– 193, DOI: 10.1016/j.colsurfb.2017.05.025
  77
  Elaboration of antibacterial plastic surfaces by a combination of antiadhesive and biocidal coatings of natural products
  Paris, Jean-Baptiste; Seyer, Damien; Jouenne, Thierry; Thebault, Pascal
  Colloids and Surfaces, B: Biointerfaces (2017), 156 (), 186-193CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
  Antibacterial polyolefins surfaces, combining biocidal and antiadhesive properties, were elaborated by a covalent grafting of antimicrobial peptides (AMPs), able to kill adherent bacteria, on a pre-immobilized hyaluronic acid (HA) layer, able to repel the micro-organisms. Different HA activation rate for its immobilization, were used to change HA layer morphol. and no. of residual free carboxylic acid functions for AMPs grafting. Based on adhesion tests on Staphylococcus epidermidis and microscopy fluorescent observations, the presence of the two combined properties was shown to be depended on the HA activation rate. Thus, the best addn. effect was obsd. for an AMP grafting on a surface based on a high HA activation, data pointing out a decrease of the bacterial adhesion up to 99.8% and a perturbation of the bacterial membrane integrity of adhered bacteria. On the contrary, a decrease of the antibacterial activity was obsd. for an AMP grafting on a surface based on a low HA activation.
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78. 78
  Ulm, H. and Schneider, T. (2016) Targeting Bactoprenol-Coupled Cell Envelope Precursors. Appl. Microbiol. Biotechnol. 100, 7815– 7825, DOI: 10.1007/s00253-016-7732-0
  78
  Targeting bactoprenol-coupled cell envelope precursors
  Ulm, Hannah; Schneider, Tanja
  Applied Microbiology and Biotechnology (2016), 100 (18), 7815-7825CODEN: AMBIDG; ISSN:0175-7598. (Springer)
  A review. Targeting the bactoprenol-coupled cell wall precursor lipid II is a validated antibacterial strategy. In this review, selected prototype lipid II-binding antibiotics of different chem. classes are discussed. Although these compds. attack the same mol. target, they trigger nuanced and diverse cellular effects. Consequently, the mechanisms of antibacterial resistance and the likelihood of resistance development may vary substantially.
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79. 79
  Weidenmaier, C. and Peschel, A. (2008) Teichoic Acids and Related Cell-Wall Glycopolymers in Gram-Positive Physiology and Host Interactions. Nat. Rev. Microbiol. 6, 276– 287, DOI: 10.1038/nrmicro1861
  79
  Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions
  Weidenmaier, Christopher; Peschel, Andreas
  Nature Reviews Microbiology (2008), 6 (4), 276-287CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
  A review. Most Gram-pos. bacteria incorporate membrane- or peptidoglycan-attached carbohydrate-based polymers into their cell envelopes. Such cell-wall glycopolymers (CWGs) often have highly variable structures and have crucial roles in protecting, connecting and controlling the major envelope constituents. Further important roles of CWGs in host-cell adhesion, inflammation and immune activation have also been described in recent years. Identifying and harnessing highly conserved or species-specific structural features of CWGs offers excellent opportunities for developing new antibiotics, vaccines and diagnostics for use in the fight against severe infectious diseases, such as sepsis, pneumonia, anthrax and tuberculosis.
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80. 80
  Kepplinger, B., Morton-Laing, S., Seistrup, K. H., Marrs, E. C. L., Hopkins, A. P., Perry, J. D., Strahl, H., Hall, M. J., Errington, J., and Allenby, N. E. E. (2018) Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin. ACS Chem. Biol. 13, 207– 214, DOI: 10.1021/acschembio.7b00733
  80
  Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin
  Kepplinger, Bernhard; Morton-Laing, Stephanie; Seistrup, Kenneth Holst; Marrs, Emma Claire Louise; Hopkins, Adam Paul; Perry, John David; Strahl, Henrik; Hall, Michael John; Errington, Jeff; Ellis Allenby, Nicholas Edward
  ACS Chemical Biology (2018), 13 (1), 207-214CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  Antibiotics that interfere with the bacterial cytoplasmic membrane have long term potential for the treatment of infectious diseases, as this mode of action is anticipated to result in low resistance frequency. Vancoresmycin is an understudied natural product antibiotic consisting of a terminal tetramic acid moiety fused to a linear, highly oxygenated, stereochem. complex polyketide chain. Vancoresmycin shows min. inhibitory concns. (MICs) from 0.125 to 2 μg/mL against a range of clin. relevant, antibiotic-resistant Gram-pos. bacteria. Through a comprehensive mode-of-action study, utilizing Bacillus subtilis reporter strains, DiSC3(5) depolarization assays and fluorescence microscopy, we have shown that vancoresmycin selectively targets the cytoplasmic membrane of Gram-pos. bacteria via a non-pore forming, concn.-dependent depolarization mechanism. Whole genome sequencing of the producing strain allowed identification of the 141 kbp gene cluster encoding for vancoresmycin biosynthesis and a preliminary model for its biosynthesis. The size and complex structure of vancoresmycin could confound attempts to generate synthetic analogs. To overcome this problem and facilitate future studies, we identified, cloned and expressed the 141 kbp biosynthetic gene cluster in Streptomyces coelicolor M1152. Elucidation of the mode-of-action of vancoresmycin, together with the heterologous expression system will greatly facilitate further studies of this and related mols.
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81. 81
  Wenzel, M., Patra, M., Senges, C. H. R., Ott, I., Stepanek, J. J., Pinto, A., Prochnow, P., Vuong, C., Langklotz, S., Metzler-Nolte, N., and Bandow, J. E. (2013) Analysis of the Mechanism of Action of Potent Antibacterial Hetero-Tri-Organometallic Compounds: A Structurally New Class of Antibiotics. ACS Chem. Biol. 8, 1442– 1450, DOI: 10.1021/cb4000844
  81
  Analysis of the Mechanism of Action of Potent Antibacterial Hetero-tri-organometallic Compounds: A Structurally New Class of Antibiotics
  Wenzel, Michaela; Patra, Malay; Senges, Christoph Helmut Rudi; Ott, Ingo; Stepanek, Jennifer Janina; Pinto, Antonio; Prochnow, Pascal; Vuong, Cuong; Langklotz, Sina; Metzler-Nolte, Nils; Bandow, Julia Elisabeth
  ACS Chemical Biology (2013), 8 (7), 1442-1450CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  Two hetero-tri-organometallic compds. with potent activity against Gram-pos. bacteria including multi-resistant Staphylococcus aureus (MRSA) were identified. The compds. consist of a peptide nucleic acid backbone with an alkyne side chain, substituted with a cymantrene, a (dipicolyl)Re(CO)3 moiety, and either a ferrocene (FcPNA) or a ruthenocene (RcPNA). Comparative proteomic anal. indicates the bacterial membrane as antibiotic target structure. FcPNA accumulation in the membrane was confirmed by manganese tracing with at. absorption spectroscopy. Both organometallics disturbed several essential cellular processes taking place at the membrane such as respiration and cell wall biosynthesis, suggesting that the compds. affect membrane architecture. Correlating with enhanced antibacterial activity, oxidative stress was induced only by the ferrocene-substituted compd. The organometallics described here target the cytoplasmic membrane, a clin. proven antibacterial target structure, feature a bactericidal but non-bacteriolytic mode of action and limited cytotoxicity within the limits of soly. Thus, FcPNA represents a promising lead structure for the development of a new synthetic class of antibiotics.
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82. 82
  Andrés, M. T. and Fierro, J. F. (2010) Antimicrobial Mechanism of Action of Transferrins: Selective Inhibition of H⁺-ATPase. Antimicrob. Agents Chemother. 54, 4335– 4342, DOI: 10.1128/AAC.01620-09
  82
  Antimicrobial mechanism of action of transferrins: Selective inhibition of H+-ATPase
  Andres, Maria T.; Fierro, Jose F.
  Antimicrobial Agents and Chemotherapy (2010), 54 (10), 4335-4342CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  Two bacterial species with different metabolic features, namely, Pseudomonas aeruginosa and Lactococcus lactis, were used as a comparative exptl. model to investigate the antimicrobial target and mechanism of transferrins. In anaerobiosis, P. aeruginosa cells were not susceptible to lactoferrin (hLf) or transferrin (hTf). In aerobiosis, the cells were susceptible but O2 consumption was not modified, indicating that components of the electron transport chain (ETC) were not targeted. However, the respiratory chain inhibitor piericidin A significantly reduced the killing activity of both proteins. Moreover, 2,6-dichlorophenolindophenol (DCIP), a reducing agent that accepts electrons from the ETC coupled to H+ extrusion, made P. aeruginosa susceptible to hLf and hTf in anaerobiosis. These results indicated that active cooperation of the cell was indispensable for the antimicrobial effect. For L. lactis cells lacking an ETC, the absence of a detectable transmembrane elec. potential in hLf-treated cells suggested a loss of H+-ATPase activity. Furthermore, the inhibition of ATPase activity and H+ translocation (inverted membrane vesicles) provided direct evidence of the ability of hLf to inhibit H+-ATPase in L. lactis. The authors propose that hLf and hTf also inhibit the H+-ATPase of respiring P. aeruginosa cells. Such inhibition thereby interferes with reentry of H+ from the periplasmic space to the cytoplasm, resulting in perturbation of intracellular pH and the transmembrane proton gradient. Consistent with this hypothesis, periplasmic H+ accumulation was prevented by anaerobiosis or by piericidin A or was induced by DCIP in anaerobiosis. These results indicate that transferrins target H+-ATPase and interfere with H+ translocation, yielding a lethal effect in vitro.
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83. 83
  Azarkina, N. and Konstantinov, A. A. (2002) Stimulation of Menaquinone-Dependent Electron Transfer in the Respiratory Chain of Bacillus Subtilis by Membrane Energization. J. Bacteriol. 184, 5339– 5347, DOI: 10.1128/JB.184.19.5339-5347.2002
  83
  Stimulation of menaquinone-dependent electron transfer in the respiratory chain of Bacillus subtilis by membrane energization
  Azarkina, N.; Konstantinov, A. A.
  Journal of Bacteriology (2002), 184 (19), 5339-5347CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
  At a pH of ≤7, respiration of Bacillus subtilis cells on endogenous substrates shut down almost completely upon addn. of an uncoupler (carbonyl cyanide m-chlorophenylhydrazone [CCCP]) and a K+-ionophore (valinomycin). The same effect was obsd. with cell spheroplasts lacking the cell wall. The concn. of CCCP required for 50% inhibition of the endogenous respiration in the presence of K+-valinomycin was below 100 nM. Either CCCP or valinomycin alone was much less efficient than the combination of the two. The inhibitory effect was easily reversible and depended specifically on the H+ and K+ concns. in the medium. Similar inhibition was obsd. with respect to the redn. of the artificial electron acceptors 2,6-dichlorophenolindophenol (DCPIP) and N,N,N',N'-tetramethyl-p-phenylenediamine cation (TMPD+), which intercept reducing equiv. at the level of menaquinol. Oxidn. of the reduced DCPIP or TMPD in the bacterial cells was not sensitive to uncoupling. The same loss of the electron transfer activities as induced by the uncoupling was obsd. upon disruption of the cells during isolation of the membranes; the residual activities were not further inhibited by the uncoupler and ionophores. We conclude that the menaquinone-dependent electron transfer in the B. subtilis respiratory chain is facilitated, thermodynamically or kinetically, by membrane energization. A requirement for an energized state of the membrane is not a specific feature of succinate oxidn., as proposed in the literature, since it was also obsd. in a mutant of B. subtilis lacking succinate:quinone reductase as well as for substrates other than succinate. Possible mechanisms of the energy-dependent regulation of menaquinone-dependent respiration in B. subtilis are discussed.
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84. 84
  Schirawski, J. and Unden, G. (1998) Menaquinone-Dependent Succinate Dehydrogenase of Bacteria Catalyzes Reversed Electron Transport Driven by the Proton Potential. Eur. J. Biochem. 257, 210– 215, DOI: 10.1046/j.1432-1327.1998.2570210.x
  84
  Menaquinone-dependent succinate dehydrogenase of bacteria catalyzes reversed electron transport driven by the proton potential
  Schirawski, Jan; Unden, Gottfried
  European Journal of Biochemistry (1998), 257 (1), 210-215CODEN: EJBCAI; ISSN:0014-2956. (Springer-Verlag)
  Succinate dehydrogenases from bacteria and archaea using menaquinone (MK) as an electron acceptor (succinate/menaquinone oxidoreductases) contain, or are predicted to contain, two heme-B groups in the membrane-anchoring protein(s), located close to opposite sides of the membrane. All succinate/ubiquinone oxidoreductases, however, contain only one heme-B mol. In Bacillus subtilis and other bacteria that use MK as the respiratory quinone, the succinate oxidase activity (succinate→O2), and the succinate/menaquinone oxidoreductase activity were specifically inhibited by uncoupler (CCCP, carbonyl cyanide m-chlorophenylhydrazone) or by agents dissipating the membrane potential (valinomycin). Other parts of the respiratory chains were not affected by the agents. Succinate oxidase or succinate/ubiquinone oxidoreductase from bacteria using ubiquinone as an acceptor were not inhibited. We propose that the endergonic electron transport from succinate (Eo' = +30 mV) to MK (Eo'≃ -80mV) in succinate/menaquinone oxidoreductase includes a reversed electron transport across the cytoplasmic membrane from the inner (neg.) to the outer (pos.) side via the two heme-B groups. The reversed electron transport is driven by the proton or elec. potential, which provides the driving force for MK redn.
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85. 85
  Mesa-Arango, A. C., Trevijano-Contador, N., Roman, E., Sanchez-Fresneda, R., Casas, C., Herrero, E., Arguelles, J. C., Pla, J., Cuenca-Estrella, M., and Zaragoza, O. (2014) The Production of Reactive Oxygen Species Is a Universal Action Mechanism of Amphotericin B against Pathogenic Yeasts and Contributes to the Fungicidal Effect of This Drug. Antimicrob. Agents Chemother. 58, 6627– 6638, DOI: 10.1128/AAC.03570-14
  85
  The production of reactive oxygen species is a universal action mechanism of amphotericin B against pathogenic yeasts and contributes to the fungicidal effect of this drug
  Mesa-Arango, Ana Cecilia; Trevijano-Contador, Nuria; Roman, Elvira; Sanchez-Fresneda, Ruth; Casas, Celia; Herrero, Enrique; Arguelles, Juan Carlos; Pla, Jesus; Cuenca-Estrella, Manuel; Zaragoza, Oscar
  Antimicrobial Agents and Chemotherapy (2014), 58 (11), 6627-6638, 13 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Amphotericin B (AMB) is an antifungal drug that binds to ergosterol and forms pores at the cell membrane, causing the loss of ions. In addn., AMB induces the accumulation of reactive oxygen species (ROS), and although these mols. have multiple deleterious effects on fungal cells, their specific role in the action mechanism of AMB remains unknown. In this work, we studied the role of ROS in the action mechanism of AMB. We detd. the intracellular induction of ROS in 44 isolates of different pathogenic yeast species (Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, Candida krusei, Cryptococcus neoformans and Cryptococcus gattii). We also characterized the prodn. of ROS in AMB-resistant isolates. We found that AMB induces the formation of ROS in all the species tested. The inhibition of the mitochondrial respiratory chain by rotenone blocked the induction of ROS by AMB and provided protection from the killing action of the antifungal. Moreover, this phenomenon was absent in strains that displayed resistance to AMB. These strains showed an alteration in the respiration rate and mitochondrial membrane potential and also had higher catalase activity than that of the AMB-susceptible strains. Consistently, AMB failed to induce protein carbonylation in the resistant strains. Our data demonstrate that the prodn. of ROS by AMB is a universal and important action mechanism that is correlated with the fungicidal effect and might explain the low rate of resistance to the mol. Finally, these data provide an opportunity to design new strategies to improve the efficacy of this antifungal.
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86. 86
  Nagao, T., Nakayama-Imaohji, H., Elahi, M., Tada, A., Toyonaga, E., Yamasaki, H., Okazaki, K., Miyoshi, H., Tsuchiya, K., and Kuwahara, T. (2018) Lhistidine Augments the Oxidative Damage against Gram-negative Bacteria by Hydrogen Peroxide. Int. J. Mol. Med. 41, 2847– 2854, DOI: 10.3892/ijmm.2018.3473
  86
  L-histidine augments the oxidative damage against Gram-negative bacteria by hydrogen peroxide
  Nagao, Tamiko; Nakayama-Imaohji, Haruyuki; Elahi, Miad; Tada, Ayano; Toyonaga, Emika; Yamasaki, Hisashi; Okazaki, Katsuichiro; Miyoshi, Hirokazu; Tsuchiya, Koichiro; Kuwahara, Tomomi
  International Journal of Molecular Medicine (2018), 41 (5), 2847-2854CODEN: IJMMFG; ISSN:1791-244X. (Spandidos Publications Ltd.)
  Excessive damage to DNA and lipid membranes by reactive oxygen species reduces the viability of bacteria. In the present study, the proliferation of recA-deficient Escherichia coli strains was revealed to be inhibited by 1% L-histidine under aerobic conditions. This inhibition of proliferation was not obsd. under anaerobic conditions, indicating that L-histidine enhances oxidative DNA damage to E. coli cells. Reverse transcription-quant. polymerase chain reaction anal. demonstrated that the expression of recA in E. coli MG1655 increased ∼7-fold following treatment with 10 mM hydrogen peroxide (H2O2) plus 1% L-histidine, compared with that following exposure to H2O2 alone. L-histidine increased the genomic fragmentation of E. coli MG1655 following exposure to H2O2. In addn., L-histidine increased the generation of intracellular hydroxyl radicals in the presence of H2O2 in E. coli cells. Next, our group investigated the disinfection properties of the H2O2 and L-histidine combination. The combination of 100 mM H2O2 and 1.0% L-histidine significantly reduced the no. of viable cells of extended-spectrum-β-lactamase-producing E. coli and multidrug-resistant Pseudomonas aeruginosa, and this treatment was more effective than 100 mM H2O2 alone, but this effect was not obsd. in methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium. The combination of L-histidine and H2O2 may be a useful strategy to selectively increase the microbicidal activity of oxidative agents against Gram-neg. bacteria.
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87. 87
  Beavers, W. N. and Skaar, E. P. (2016) Neutrophil-Generated Oxidative Stress and Protein Damage in Staphylococcus Aureus. Pathog. Dis. 74, ftw060, DOI: 10.1093/femspd/ftw060
  There is no corresponding record for this reference.
88. 88
  Kirstein, J., Hoffmann, A., Lilie, H., Schmidt, R., Rubsamen-Waigmann, H., Brotz-Oesterhelt, H., Mogk, A., and Turgay, K. (2009) The Antibiotic ADEP Reprogrammes ClpP, Switching It from a Regulated to an Uncontrolled Protease. EMBO Mol. Med. 1, 37– 49, DOI: 10.1002/emmm.200900002
  88
  The antibiotic ADEP reprogrammes ClpP, switching it from a regulated to an uncontrolled protease
  Kirstein, Janine; Hoffmann, Anja; Lilie, Hauke; Schmidt, Ronny; Ruebsamen-Waigmann, Helga; Broetz-Oesterhelt, Heike; Mogk, Axel; Turgay, Kuersad
  EMBO Molecular Medicine (2009), 1 (1), 37-49CODEN: EMMMAM; ISSN:1757-4684. (John Wiley & Sons Ltd.)
  A novel class of antibiotic acyldepsipeptides (designated ADEPs) exerts its unique antibacterial activity by targeting the peptidase caseinolytic protease P (ClpP). ClpP forms proteolytic complexes with heat shock proteins (Hsp100) that select and process substrate proteins for ClpP-mediated degrdn. Here, we analyze the mol. mechanism of ADEP action and demonstrate that ADEPs abrogate ClpP interaction with cooperating Hsp100 ATPases (ATPases). Consequently, ADEP treated bacteria are affected in ClpP-dependent general and regulatory proteolysis. At the same time, ADEPs also activate ClpP by converting it from a tightly regulated peptidase, which can only degrade short peptides, into a proteolytic machinery that recognizes and degrades unfolded polypeptides. In vivo nascent polypeptide chains represent the putative primary target of ADEP-activated ClpP, providing a rationale for the antibacterial activity of the ADEPs. Thus, ADEPs cause a complete functional reprogramming of the Clp-protease complex.
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89. 89
  Klappenbach, J. A., Saxman, P. R., Cole, J. R., and Schmidt, T. M. (2001) Rrndb: The Ribosomal RNA Operon Copy Number Database. Nucleic Acids Res. 29, 181– 184, DOI: 10.1093/nar/29.1.181
  89
  rrndb: the ribosomal RNA operon copy number database
  Klappenbach, Joel A.; Saxman, Paul R.; Cole, James R.; Schmidt, Thomas M.
  Nucleic Acids Research (2001), 29 (1), 181-184CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
  The RRNA Operon Copy No. Database (rrndb) is an Internet-accessible database contg. annotated information on rRNA operon copy no. among prokaryotes. Gene redundancy is uncommon in prokaryotic genomes, yet the rRNA genes can vary from one to as many as 15 copies. Despite the widespread use of 16S rRNA gene sequences for identification of prokaryotes, information on the no. and sequence of individual rRNA genes in a genome is not readily accessible. In an attempt to understand the evolutionary implications of rRNA operon redundancy, we have created a phylogenetically arranged report on rRNA gene copy no. for a diverse collection of prokaryotic microorganisms. Each entry (organism) in the rrndb contains detailed information linked directly to external websites including the Ribosomal Database Project, GenBank, PubMed and several culture collections. Data contained in the rrndb will be valuable to researchers investigating microbial ecol. and evolution using 16S rRNA gene sequences. The rrndb web site is directly accessible on the WWW at http://rrndb.cme.msu.edu.
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90. 90
  Spratt, B. G. (1977) Properties of the Penicillin-Binding Proteins of Escherichia Coli K12. Eur. J. Biochem. 72, 341– 352, DOI: 10.1111/j.1432-1033.1977.tb11258.x
  90
  Properties of the penicillin-binding proteins of Escherichia coli K12
  Spratt, Brian G.
  European Journal of Biochemistry (1977), 72 (2), 341-52CODEN: EJBCAI; ISSN:0014-2956.
  C14-labeled benzyl penicillin (I) [61-33-6] bound to 6 proteins with mol. wts. of between 40000-91000 in the inner membrane of E. coli. Two addnl. binding proteins with mol. wts of 29000 and 32000 were sometimes detected. All proteins were accessible to I-14C in whole cells. Proteins 5 and 6 released bound I with half times of 5 and 19 min at 30° but the other binding proteins showed <50% release during a 60-min period at 30°. The rate of release of bound penicillin from some of the proteins was greatly stimulated by 2-mercaptoethanol and neutral hydroxylamine. Release of I-14C did not occur if the binding proteins were denatured in anionic detergent and so was probably enzymic. β-Lactams bound to either of a range of unlabeled penicillins and cephalosporins were studied by measuring their competition for the binding of I-14C to the 6 penicillin-binding proteins. Penicillins bound to all 6 proteins but that at least some cephalosporins failed to bind, or bound very slowly, to proteins 2, 5, and 6, although they bound to the other proteins. Since these cephalosporins inhibited cell division and caused cell lysis at concns. where no binding to proteins 2, 5, and 6 was detected, these latter proteins are apparently not the targets at which β-lactams bind to elicit the above physiol. responses.
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91. 91
  Denome, S. A., Elf, P. K., Henderson, T. A., Nelson, D. E., and Young, K. D. (1999) Escherichia Coli Mutants Lacking All Possible Combinations of Eight Penicillin Binding Proteins: Viability, Characteristics, and Implications for Peptidoglycan Synthesis. J. Bacteriol. 181, 3981– 3993, DOI: 10.1128/JB.181.13.3981-3993.1999
  91
  Escherichia coli mutants lacking all possible combinations of eight penicillin binding proteins: viability, characteristics, and implications for peptidoglycan synthesis
  Denome, Sylvia A.; Elf, Pamela K.; Henderson, Thomas A.; Nelson, David E.; Young, Kevin D.
  Journal of Bacteriology (1999), 181 (13), 3981-3993CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
  The penicillin binding proteins (PBPs) synthesize and remodel peptidoglycan, the structural component of the bacterial cell wall. Much is known about the biochem. of these proteins, but little is known about their biol. roles. To better understand the contributions these proteins make to the physiol. of Escherichia coli, we constructed 192 mutants from which eight PBP genes were deleted in every possible combination. The genes encoding PBPs 1a, 1b, 4, 5, 6, and 7, AmpC, and AmpH were cloned, and from each gene an internal coding sequence was removed and replaced with a kanamycin resistance cassette flanked by two res sites from plasmid RP4. Deletion of individual genes was accomplished by transferring each interrupted gene onto the chromosome of E. coli via λ phage transduction and selecting for kanamycin-resistant recombinants. Afterwards, the kanamycin resistance cassette was removed from each mutant strain by supplying ParA resolvase in trans, yielding a strain in which a long segment of the original PBP gene was deleted and replaced by an 8-bp res site. These kanamycin-sensitive mutants were used as recipients in further rounds of replacement mutagenesis, resulting in a set of strains lacking from one to seven PBPs. In addn., the dacD gene was deleted from two septuple mutants, creating strains lacking eight genes. The only deletion combinations not produced were those lacking both PBPs 1a and 1b because such a combination is lethal. Surprisingly, all other deletion mutants were viable even though, at the extreme, 8 of the 12 known PBPs had been eliminated. Furthermore, when both PBPs 2 and 3 were inactivated by the β-lactams mecillinam and aztreonam, resp., several mutants did not lyse but continued to grow as enlarged spheres, so that one mutant synthesized osmotically resistant peptidoglycan when only 2 of 12 PBPs (PBPs 1b and 1c) remained active. These results have important implications for current models of peptidoglycan biosynthesis, for understanding the evolution of the bacterial sacculus, and for interpreting results derived by mutating unknown open reading frames in genome projects. In addn., members of the set of PBP mutants will provide excellent starting points for answering fundamental questions about other aspects of cell wall metab.
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92. 92
  Kocaoglu, O. and Carlson, E. E. (2015) Profiling of β-Lactam Selectivity for Penicillin-Binding Proteins in Escherichia Coli Strain DC2. Antimicrob. Agents Chemother. 59, 2785– 2790, DOI: 10.1128/AAC.04552-14
  92
  Profiling of β-lactam selectivity for penicillin-binding proteins in Escherichia coli strain DC2
  Kocaoglu, Ozden; Carlson, Erin E.
  Antimicrobial Agents and Chemotherapy (2015), 59 (5), 2785-2790CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Penicillin-binding proteins (PBPs) are integral players in bacterial cell division, and their catalytic activities can be monitored with β-lactam-contg. chem. probes. Compds. that target a single PBP could provide important information about the specific role(s) of each enzyme, making identification of such mols. important. The authors evaluated 22 com. available β-lactams for inhibition of the PBPs in live Escherichia coli strain DC2. Whole cells were titrated with β-lactam antibiotics and subsequently incubated with a fluorescent penicillin deriv., Bocillin-FL (Boc-FL), to label uninhibited PBPs. Protein visualization was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) sepn. and fluorescent scanning. The examd. β-lactams exhibited diverse PBP selectivities, with amdinocillin (mecillinam) showing selectivity for PBP2, aztreonam, piperacillin, cefuroxime, cefotaxime, and ceftriaxone for PBP3, and amoxicillin and cephalexin for PBP4. The remaining β-lactams did not block any PBPs in the DC2 strain of E. coli or inhibited more than one PBP at all examd. concns. in this Gram-neg. organism.
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93. 93
  Du, W., Brown, J. R., Sylvester, D. R., Huang, J., Chalker, A. F., So, C. Y., Holmes, D. J., Payne, D. J., and Wallis, N. G. (2000) Two Active Forms of UDP-N-Acetylglucosamine Enolpyruvyl Transferase in Gram-Positive Bacteria. J. Bacteriol. 182, 4146– 4152, DOI: 10.1128/JB.182.15.4146-4152.2000
  93
  Two active forms of UDP-N-acetylglucosamine enolpyruvyl transferase in gram-positive bacteria
  Du, Wensheng; Brown, James R.; Sylvester, Daniel R.; Huang, Jianzhong; Chalker, Alison F.; So, Chi Y.; Holmes, David J.; Payne, David J.; Wallis, Nicola G.
  Journal of Bacteriology (2000), 182 (15), 4146-4152CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
  Gene sequences encoding the enzymes UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) from many bacterial sources were analyzed. It was shown that whereas gram-neg. bacteria have only one murA gene, gram-pos. bacteria have two distinct genes encoding these enzymes which have possibly arisen from gene duplication. The two murA genes of the gram-pos. organism Streptococcus pneumoniae were studied further. Each of the murA genes was individually inactivated by allelic replacement. In each case, the organism was viable despite losing one of its murA genes. However, when attempts were made to construct a double-deletion strain, no mutants were obtained. This indicates that both genes encode active enzymes that can substitute for each other, but that the presence of a MurA function is essential to the organism. The two genes were further cloned and over-expressed, and the enzymes they encode were purified. Both enzymes catalyzed the transfer of enolpyruvate from phosphoenolpyruvate to UDP-N-acetylglucosamine, confirming they are both active UDP-N-acetylglucosamine enolpyruvyl transferases. The catalytic parameters of the two enzymes were similar, and they were both inhibited by the antibiotic fosfomycin.
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94. 94
  Noda, M., Kawahara, Y., Ichikawa, A., Matoba, Y., Matsuo, H., Lee, D.-G., Kumagai, T., and Sugiyama, M. (2004) Self-Protection Mechanism in D-Cycloserine-Producing Streptomyces Lavendulae. Gene Cloning, Characterization, and Kinetics of Its Alanine Racemase and D-Alanyl-D-Alanine Ligase, Which Are Target Enzymes of D-Cycloserine. J. Biol. Chem. 279, 46143– 46152, DOI: 10.1074/jbc.M404603200
  94
  Self-protection Mechanism in D-Cycloserine-producing Streptomyces lavendulae. Gene cloning, characterization, and kinetics of its alanine racemase and D-alanyl-D-alanine ligase, which are target enzymes of D-cycloserine
  Noda, Masafumi; Kawahara, Yumi; Ichikawa, Azusa; Matoba, Yasuyuki; Matsuo, Hiroaki; Lee, Dong-Geun; Kumagai, Takanori; Sugiyama, Masanori
  Journal of Biological Chemistry (2004), 279 (44), 46143-46152CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  An antibiotic, D-cycloserine (DCS), inhibits the catalytic activities of alanine racemase (ALR) and D-alanyl-D-alanine ligase (DDL), which are necessary for the biosynthesis of the bacterial cell wall. In this study, we cloned both genes encoding ALR and DDL, designated alrS and ddlS, resp., from DCS-producing Streptomyces lavendulae ATCC25233. Each gene product was purified to homogeneity and characterized. Escherichia coli, transformed with a pET vector carrying alrS or ddlS, displays higher resistance to DCS than the same host carrying the E. coli ALR- or DDL-encoded gene inserted into the pET vector. Although the S. lavendulae DDL was competitively inhibited by DCS, the Ki value (920 μM) was obviously higher (40∼100-fold) than those for E. coli DdlA (9 μM) or DdlB (27 μM). The high Ki value of the S. lavendulae DDL suggests that the enzyme may be a self-resistance determinant in the DCS-producing microorganism. Kinetic studies for the S. lavendulae ALR suggest that the time-dependent inactivation rate of the enzyme by DCS is absolutely slower than that of the E. coli ALR. We conclude that ALR from DCS-producing S. lavendulae is also one of the self-resistance determinants.
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95. 95
  Rudolf, J. D., Dong, L.-B., and Shen, B. (2017) Platensimycin and Platencin: Inspirations for Chemistry, Biology, Enzymology, and Medicine. Biochem. Pharmacol. 133, 139– 151, DOI: 10.1016/j.bcp.2016.11.013
  95
  Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine
  Rudolf, Jeffrey D.; Dong, Liao-Bin; Shen, Ben
  Biochemical Pharmacology (Amsterdam, Netherlands) (2017), 133 (), 139-151CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
  Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clin. antibiotics. Their unparalleled structural and chem. diversities provide a basis to investigate fundamental biol. processes while providing access to a tremendous amt. of chem. space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biol. activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis. The elucidation of their unique biochem. mode of action, structure-activity relationships, and pharmacokinetics is presented to highlight key aspects of their biol. activities. It then presents an overview of how microbial genomics has impacted the field of PTM and PTN and revealed paradigm-shifting discoveries in terpenoid biosynthesis, fatty acid metab., and antibiotic and antidiabetic therapies. It concludes with a discussion covering the future perspectives of PTM and PTN in regard to natural products discovery, bacterial diterpenoid biosynthesis, and the pharmaceutical promise of PTM and PTN as antibiotics and for the treatment of metabolic disorders. PTM and PTN have inspired new discoveries in chem., biol., enzymol., and medicine and will undoubtedly continue to do so.
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96. 96
  Jayasuriya, H., Herath, K. B., Zhang, C., Zink, D. L., Basilio, A., Genilloud, O., Diez, M. T., Vicente, F., Gonzalez, I., Salazar, O., Pelaez, F., Cummings, R., Ha, S., Wang, J., and Singh, S. B. (2007) Isolation and Structure of Platencin: A FabH and FabF Dual Inhibitor with Potent Broad-Spectrum Antibiotic Activity. Angew. Chem., Int. Ed. 46, 4684– 4688, DOI: 10.1002/anie.200701058
  96
  Isolation and structure of Platencin: a FabH and FabF dual inhibitor with potent broad-spectrum antibiotic activity
  Jayasuriya, Hiranthi; Herath, Kithsiri B.; Zhang, Chaowei; Zink, Deborah L.; Basilio, Angela; Genilloud, Olga; Diez, Maria Teresa; Vicente, Francisca; Gonzalez, Ignacio; Salazar, Oscar; Pelaez, Fernando; Cummings, Richard; Ha, Sookhee; Wang, Jun; Singh, Sheo B.
  Angewandte Chemie, International Edition (2007), 46 (25), 4684-4688CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Two birds with one stone: platencin is a novel and potent broad-spectrum Gram-pos. antibiotic. Whereas platensimycin is a selective inhibitor of FabF, platencin exerts its activity by a novel mode of action by dual inhibition of FabH and FabF. The authors describe the isolation, structure elucidation, and addnl. biol. activity of platencin as well as a modeling-based rationale for the differences in activity between platencin and platensimycin.
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97. 97
  Wang, J., Kodali, S., Lee, S. H., Galgoci, A., Painter, R., Dorso, K., Racine, F., Motyl, M., Hernandez, L., Tinney, E. (2007) Discovery of Platencin, a Dual FabF and FabH Inhibitor with in Vivo Antibiotic Properties. Proc. Natl. Acad. Sci. U. S. A. 104, 7612– 7616, DOI: 10.1073/pnas.0700746104
  97
  Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties
  Wang, Jun; Kodali, Srinivas; Lee, Sang Ho; Galgoci, Andrew; Painter, Ronald; Dorso, Karen; Racine, Fred; Motyl, Mary; Hernandez, Lorraine; Tinney, Elizabeth; Colletti, Steven L.; Herath, Kithsiri; Cummings, Richard; Salazar, Oscar; Gonzalez, Ignacio; Basilio, Angela; Vicente, Francisca; Genilloud, Olga; Pelaez, Fernando; Jayasuriya, Hiranthi; Young, Katherine; Cully, Doris F.; Singh, Sheo B.
  Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (18), 7612-7616CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently the authors reported the discovery of platensimycin by screening natural product exts. using a target-based whole-cell strategy with antisense silencing technol. in concert with cell free biochem. validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chem. and biol. related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-pos. antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Platencin shows potent in vivo efficacy without any obsd. toxicity. It targets 2 essential proteins, β-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC50 values of 1.95 and 3.91 μg/mL, resp., whereas platensimycin targets only FabF (IC50 = 0.13 μg/mL) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by this antisense differential sensitivity whole-cell screening paradigm.
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98. 98
  Velkov, T., Roberts, K. D., Nation, R. L., Thompson, P. E., and Li, J. (2013) Pharmacology of Polymyxins: New Insights into an “old” Class of Antibiotics. Future Microbiol. 8, 711– 724, DOI: 10.2217/fmb.13.39
  98
  Pharmacology of polymyxins: new insights into an old' class of antibiotics
  Velkov, Tony; Roberts, Kade D.; Nation, Roger L.; Thompson, Philip E.; Li, Jian
  Future Microbiology (2013), 8 (6), 711-724CODEN: FMUIAR; ISSN:1746-0913. (Future Medicine Ltd.)
  A review. Increasing antibiotic resistance in Gram-neg. bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these superbugs' in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-neg. bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chem., mechanisms of antibacterial activity and resistance, structure-activity relationships and pharmacokinetics/pharmacodynamics. In the Bad Bugs, No Drugs' era, we must pursue structure-activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-neg. superbugs'. Before new antibiotics become available, we must optimize the clin. use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.
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99. 99
  Fu, L., Wan, M., Zhang, S., Gao, L., and Fang, W. (2020) Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer. Biophys. J. 118, 138– 150, DOI: 10.1016/j.bpj.2019.11.008
  99
  Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer
  Fu, Lei; Wan, Mingwei; Zhang, Shan; Gao, Lianghui; Fang, Weihai
  Biophysical Journal (2020), 118 (1), 138-150CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
  Multidrug-resistant Gram-neg. bacteria have increased the prevalence of a variety of serious diseases in modern times. Polymyxins are used as the last-line therapeutic options for the treatment of infections. However, the mechanism of action of polymyxins remains in dispute. In this work, we used a coarse-grained mol. dynamics simulation to investigate the mechanism of the cationic antimicrobial peptide polymyxin B (PmB) interacting with both the inner and outer membrane models of bacteria. Our results show that the binding of PmB disturbs the outer membrane by displacing the counterions, decreasing the orientation order of the lipopolysaccharide tail, and creating more lipopolysaccharide packing defects. Upon binding onto the inner membrane, in contrast to the traditional killing mechanism that antimicrobial peptides usually use to induce holes in the membrane, PmBs do not permeabilize the inner membrane but stiffen it by filling up the lipid packing defect, increasing the lipid tail order and the membrane bending rigidity as well as restricting the lipid diffusion. PmBs also mediate intermembrane contact and adhesion. These joint effects suggest that PmBs deprive the biol. activity of Gram-neg. bacteria by sterilizing the cell.
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100. 100
  Deris, Z. Z., Akter, J., Sivanesan, S., Roberts, K. D., Thompson, P. E., Nation, R. L., Li, J., and Velkov, T. (2014) A Secondary Mode of Action of Polymyxins against Gram-Negative Bacteria Involves the Inhibition of NADH-Quinone Oxidoreductase Activity. J. Antibiot. 67, 147– 151, DOI: 10.1038/ja.2013.111
  100
  A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity
  Deris, Zakuan Z.; Akter, Jesmin; Sivanesan, Sivashangarie; Roberts, Kade D.; Thompson, Philip E.; Nation, Roger L.; Li, Jian; Velkov, Tony
  Journal of Antibiotics (2014), 67 (2), 147-151CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
  Polymyxin B and colistin were examd. for their ability to inhibit the type II NADH-quinone oxidoreductases (NDH-2) of three species of Gram-neg. bacteria. Polymyxin B and colistin inhibited the NDH-2 activity in prepns. from all of the isolates in a concn.-dependent manner. The mechanism of NDH-2 inhibition by polymyxin B was investigated in detail with Escherichia coli inner membrane prepns. and conformed to a mixed inhibition model with respect to ubiquinone-1 and a non-competitive inhibition model with respect to NADH. These suggest that the inhibition of vital respiratory enzymes in the bacterial inner membrane represents one of the secondary modes of action for polymyxins.
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101. 101
  Stuart, M. C., Kouimtzi, M., and Hill, S. (2009) WHO Model Formulary 2008, WHO, Geneva.
  There is no corresponding record for this reference.
102. 102
  Arbiser, J. L. and Moschella, S. L. (1995) Clofazimine: A Review of Its Medical Uses and Mechanisms of Action. J. Am. Acad. Dermatol. 32, 241– 247, DOI: 10.1016/0190-9622(95)90134-5
  102
  Clofazimine: a review of its medical uses and mechanisms of action
  Arbiser J L; Moschella S L
  Journal of the American Academy of Dermatology (1995), 32 (2 Pt 1), 241-7 ISSN:0190-9622.
  Clofazimine has been in clinical use for almost 40 years, but little is known of its mechanism of action. The primary indication for clofazimine is multibacillary leprosy, but it is useful in several infectious and noninfectious diseases, such as typical myocobacterial infections, rhinoscleroma, pyoderma gangrenosum, necrobiosis lipoidica, severe acne, pustular psoriasis, and discoid lupus erythematosus. Postulated mechanisms of action include intercalation of clofazimine with bacterial DNA and increasing levels of cellular phospholipase A2. Clinical experience, possible mechanisms of action, and side effects of clofazimine are summarized.
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103. 103
  Lesnik, U., Lukezic, T., Podgorsek, A., Horvat, J., Polak, T., Sala, M., Jenko, B., Harmrolfs, K., Ocampo-Sosa, A., Martinez-Martinez, L., Herron, P. R., Fujs, S., Kosec, G., Hunter, I. S., Muller, R., and Petkovic, H. (2015) Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering. Angew. Chem., Int. Ed. 54, 3937– 3940, DOI: 10.1002/anie.201411028
  103
  Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering
  Lesnik, Urska; Lukezic, Tadeja; Podgorsek, Ajda; Horvat, Jaka; Polak, Tomaz; Sala, Martin; Jenko, Branko; Harmrolfs, Kirsten; Ocampo-Sosa, Alain; Martinez-Martinez, Luis; Herron, Paul R.; Fujs, Stefan; Kosec, Gregor; Hunter, Iain S.; Mueller, Rolf; Petkovic, Hrvoje
  Angewandte Chemie, International Edition (2015), 54 (13), 3937-3940CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacol. properties could not be addressed at the time. It is demonstrated here that reviving such compds. through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad-spectrum antibiotic lead was generated with significantly improved activity, including against all Gram-neg. pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chem. modification, it is a platform for further development through medicinal chem. and genetic engineering.
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104. 104
  Herrmann, J., Lukezic, T., Kling, A., Baumann, S., Huttel, S., Petkovic, H., and Muller, R. (2016) Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies. Curr. Top. Microbiol. Immunol. 398, 339– 363, DOI: 10.1007/82_2016_498
  104
  Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies
  Herrmann, Jennifer; Lukezic, Tadeja; Kling, Angela; Baumann, Sascha; Huettel, Stephan; Petkovic, Hrvoje; Mueller, Rolf
  Current Topics in Microbiology and Immunology (2016), 398 (How to Overcome the Antibiotic Crisis), 339-363CODEN: CTMIA3; ISSN:2196-9965. (Springer GmbH)
  Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Center for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery. In particular, we will exemplarily illustrate three approaches: (1) Current sources for novel compds. are mainly soil-dwelling bacteria. In the course of our antimicrobial discovery program, a biodiverse collection of myxobacterial strains has been established and screened for antibiotic activities. Based on this effort, one successful example is presented in this chapter: Antibacterial cystobactamids were discovered and their mol. target, the DNA gyrase, was identified soon after the anal. of myxobacterial self-resistance making use of the information found in the resp. biosynthesis gene cluster. (2) Besides our focus on novel natural products, we also apply strategies to further develop either neglected drugs or widely used antibiotics for which development of resistance in the clin. setting is an issue: Antimycobacterial griselimycins were first described in the 1960s but their development and use in tuberculosis therapy was not further pursued. We show how a griselimycin deriv. with improved pharmacokinetic properties and enhanced potency against Mycobacterium tuberculosis revealed and validated a novel target for antibacterial therapy, the DNA sliding clamp. (3) In a third approach, biosynthetic engineering was used to modify and optimize natural products regarding their pharmaceutical properties and their prodn. scale: The atypical tetracycline chelocardin is a natural product scaffold that was modified to yield a more potent deriv. exhibiting activity against multidrug-resistant pathogens. This was achieved by genetic engineering of the producer strain and the resulting compd. is now subject to further optimization by medicinal chem. approaches.
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105. 105
  Stepanek, J. J., Lukezic, T., Teichert, I., Petkovic, H., and Bandow, J. E. (2016) Dual Mechanism of Action of the Atypical Tetracycline Chelocardin. Biochim. Biophys. Acta, Proteins Proteomics 1864, 645– 654, DOI: 10.1016/j.bbapap.2016.03.004
  105
  Dual mechanism of action of the atypical tetracycline chelocardin
  Stepanek, Jennifer J.; Lukezic, Tadeja; Teichert, Ines; Petkovic, Hrvoje; Bandow, Julia E.
  Biochimica et Biophysica Acta, Proteins and Proteomics (2016), 1864 (6), 645-654CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B. V.)
  FR OLClassical tetracyclines targeting the protein biosynthesis machinery are commonly applied in human and veterinary medicine. OLtThe development and spread of resistance seriously compromise the successful treatment of bacterial infections. The atypical tetracycline chelocardin holds promise as it retains activity against tetracycline-resistant strains. It has been suggested that chelocardin targets the bacterial membrane, thus differing in mode of action from that of classical tetracyclines. The authors investigated the mechanism of action of chelocardin using global proteome anal. The proteome profiles after sublethal chelocardin stress were compared to a ref. compendium contg. antibiotic response profiles of Bacillus subtilis. This approach revealed a concn.-dependent dual mechanism of action. At low concns., like classical tetracyclines, chelocardin induces the proteomic signature for peptidyltransferase inhibition, demonstrating that protein biosynthesis inhibition is the dominant physiol. challenge. At higher concns., B. subtilis mainly responds to membrane stress indicating that at clin. relevant concns. the membrane is the main antibiotic target of chelocardin. Studying the effects on the membrane in more detail, it was found that chelocardin causes membrane depolarization but does not lead to formation of large pores. It is concluded that at growth inhibiting doses chelocardin not only targets protein biosynthesis but also corrupts the integrity of the bacterial membrane. This dual mechanism of action might prove beneficial in slowing the development of new resistance mechanisms against this atypical tetracycline.
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106. 106
  Herskovits, A. A. and Bibi, E. (2000) Association of Escherichia Coli Ribosomes with the Inner Membrane Requires the Signal Recognition Particle Receptor but Is Independent of the Signal Recognition Particle. Proc. Natl. Acad. Sci. U. S. A. 97, 4621– 4626, DOI: 10.1073/pnas.080077197
  106
  Association of Escherichia coli ribosomes with the inner membrane requires the signal recognition particle receptor but is independent of the signal recognition particle
  Herskovits, Anat A.; Bibi, Eitan
  Proceedings of the National Academy of Sciences of the United States of America (2000), 97 (9), 4621-4626CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  In mammalian cells, as well as Escherichia coli, ribosomes translating membrane proteins interact cotranslationally with translocons in the membrane, and this interaction is essential for proper insertion of nascent polypeptides into the membrane. Both the signal recognition particle (SRP) and its receptor (SR) are required for functional assocn. of ribosomes translating integral membrane proteins with the translocon. Herein, we confirm that membrane targeting of E. coli ribosomes requires the prokaryotic SRα homolog FtsY in vivo. Surprisingly, however, depletion of the E. coli SRP54 homolog (Ffh) has no significant effect on binding of ribosomes to the membrane, although Ffh depletion is detrimental to growth. These and other observations suggest that, in E. coli, SRP may operate downstream of SR-mediated targeting of ribosomes to the plasma membrane.
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107. 107
  Ruhr, E. and Sahl, H. G. (1985) Mode of Action of the Peptide Antibiotic Nisin and Influence on the Membrane Potential of Whole Cells and on Cytoplasmic and Artificial Membrane Vesicles. Antimicrob. Agents Chemother. 27, 841– 845, DOI: 10.1128/AAC.27.5.841
  107
  Mode of action of the peptide antibiotic nisin and influence on the membrane potential of whole cells and on cytoplasmic and artificial membrane vesicles
  Ruhr, Elke; Sahl, Hans G.
  Antimicrobial Agents and Chemotherapy (1985), 27 (5), 841-5CODEN: AMACCQ; ISSN:0066-4804.
  The peptide antibiotic nisin caused a rapid efflux of amino acids and Rb+ from the cytoplasm of gram-pos. bacteria (Staphylococcus cohnii 22, Bacillus subtilis W 23, Micrococcus luteus ATCC 4698, and Streptococcus zymogenes 24). The antibiotic strongly decreased the membrane potential of cells as judged by the distribution of the lipophilic tetraphenylphosphonium cation. Ascorbate-phenazine methosulfate-driven transport of L-proline by cytoplasmic membrane vesicles was blocked after addn. of nisin, and accumulated amino acids were released from the vesicles. Soybean phospholipid (asolectin) vesicles were not affected by nisin. Apparently, the cytoplasmic membrane is the primary target and membrane disruption accounts for the bactericidal action of nisin.
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108. 108
  Breukink, E., Wiedemann, I., van Kraaij, C., Kuipers, O. P., Sahl, H. G., and de Kruijff, B. (1999) Use of the Cell Wall Precursor Lipid II by a Pore-Forming Peptide Antibiotic. Science 286, 2361– 2364, DOI: 10.1126/science.286.5448.2361
  108
  Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic
  Breukink, E.; Wiedemann, I.; Van Kraaij, C.; Kuipers, O. P.; Sahl, H.-G.; De Kruijff, B.
  Science (Washington, D. C.) (1999), 286 (5448), 2361-2364CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Resistance to antibiotics is increasing in some groups of clin. important pathogens. For instance, high vancomycin resistance has emerged in enterococci. Promising alternative antibiotics are the peptide antibiotics, abundant in host defense systems, which kill their targets by permeabilizing the plasma membrane. These peptides generally do not act via specific receptors and are active in the micromolar range. Here it is shown that vancomycin and the antibacterial peptide nisin Z use the same target: the membrane-anchored cell wall precursor lipid II. Nisin combines high affinity for lipid II with its pore-forming ability, thus causing the peptide to be highly active (in the nanomolar range).
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109. 109
  Hasper, H. E., de Kruijff, B., and Breukink, E. (2004) Assembly and Stability of Nisin-Lipid II Pores. Biochemistry 43, 11567– 11575, DOI: 10.1021/bi049476b
  109
  Assembly and Stability of Nisin-Lipid II Pores
  Hasper, Hester Emilie; De Kruijff, Ben; Breukink, Eefjan
  Biochemistry (2004), 43 (36), 11567-11575CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  The peptide antibiotic nisin was the first reported example of an antibiotic that kills bacteria via targeted pore formation. The specific target of nisin is Lipid II, an essential intermediate in the bacterial cell-wall synthesis. High-affinity binding of the antibiotic to Lipid II is followed by rapid permeabilization of the membrane. Here, we investigated the assembly and stability of nisin-Lipid II pore complexes by means of pyrene fluorescence and CD. We demonstrated that nisin uses all available Lipid II mols. in the membrane to form pore complexes. The pore complexes have a uniform structure and consist of 8 nisin and 4 Lipid II mols. Moreover, the pores displayed a remarkable stability, because they were able to resist the solubilization of the membrane environment by mild detergents. Similar expts. with [N20P/M21P]nisin showed that the hinge region is essential for the assembly into stable pore complexes. The new insights were used to propose a refined model for nisin pore formation.
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110. 110
  ’t Hart, P., Oppedijk, S. F., Breukink, E., and Martin, N. I. (2016) New Insights into Nisin’s Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues. Biochemistry 55, 232– 237, DOI: 10.1021/acs.biochem.5b01173
  110
  New Insights into Nisin's Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues
  't Hart, Peter; Oppedijk, Sabine F.; Breukink, Eefjan; Martin, Nathaniel I.
  Biochemistry (2016), 55 (1), 232-237CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  Nisin is the preeminent lantibiotic, and to date its antibacterial mechanism has been investigated using a variety of techniques. While nisin's lipid II-mediated mode of action is well-established, a detailed anal. of the thermodn. parameters governing this interaction has not been previously reported. We here describe an approach employing isothermal titrn. calorimetry to directly measure the affinity of nisin for lipid II and a no. of synthetic lipid II precursors and analogs. Our measurements confirm the pyrophosphate unit of lipid II as the primary site of nisin binding and also indicate that the complete MurNAc moiety is required for a high-affinity interaction. Addnl., we find that while the pentapeptide unit of the lipid II mol. is not required for strong binding by nisin, it does play an important role in stabilizing the subsequently formed nisin-lipid II pore complex, albeit at an entropic cost. The anchoring of lipid II in a membrane environment was also found to play a significant role in enhancing nisin binding and is required in order to achieve a high-affinity interaction.
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111. 111
  Bonev, B. B., Chan, W. C., Bycroft, B. W., Roberts, G. C., and Watts, A. (2000) Interaction of the Lantibiotic Nisin with Mixed Lipid Bilayers: A 31P and 2H NMR Study. Biochemistry 39, 11425– 11433, DOI: 10.1021/bi0001170
  111
  Interaction of the Lantibiotic Nisin with Mixed Lipid Bilayers: A 31P and 2H NMR Study
  Bonev, Boyan B.; Chan, Weng C.; Bycroft, Barrie W.; Roberts, Gordon C. K.; Watts, Anthony
  Biochemistry (2000), 39 (37), 11425-11433CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  Nisin is a pos. charged antibacterial peptide which binds to the neg. charged membranes of Gram-pos. bacteria. The initial interaction of the peptide with model membranes of neutral (phosphatidylcholine) and neg. charged (phosphatidylcholine/phosphatidylglycerol) model lipid membranes was studied using nonperturbing solid state magic angle spinning (MAS) 31P NMR and 2H wide-line NMR. In the presence of nisin, the coexistence of two bilayer lipid environments was obsd. both in charged and in neutral membranes. One lipid environment was found to be assocd. with lipid directly interacting with nisin and one with noninteracting lipid. Solid state 31P MAS NMR results show that the acidic membrane lipid component partitions preferentially into the nisin-assocd. environment. Deuterium NMR (2H NMR) of the selectively headgroup-labeled acidic lipid provides further evidence of a strong interaction between the charged lipid component and the peptide. The segregation of acidic lipid into the nisin-bound environment was quantified from 2H NMR measurements of selectively headgroup-deuterated neutral lipid. It is suggested that the obsd. lipid partitioning in the presence of nisin is driven, at least initially, by electrostatic interactions. 2H NMR measurements from chain-perdeuterated neutral lipids indicate that nisin perturbs the hydrophobic region of both charged and neutral bilayers.
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112. 112
  Christ, K., Al-Kaddah, S., Wiedemann, I., Rattay, B., Sahl, H.-G., and Bendas, G. (2008) Membrane Lipids Determine the Antibiotic Activity of the Lantibiotic Gallidermin. J. Membr. Biol. 226, 9– 16, DOI: 10.1007/s00232-008-9134-4
  112
  Membrane lipids determine the antibiotic activity of the lantibiotic gallidermin
  Christ, Katrin; Al-Kaddah, Saad; Wiedemann, Imke; Rattay, Bernd; Sahl, Hans-Georg; Bendas, Gerd
  Journal of Membrane Biology (2008), 226 (1-3), 9-16CODEN: JMBBBO; ISSN:0022-2631. (Springer)
  Lantibiotics, a group of lanthionine-contg. peptides, display their antibiotic activity by combining different killing mechanisms within one mol. The prototype lantibiotic nisin was shown to possess both inhibition of peptidoglycan synthesis and pore formation in bacterial membranes by interacting with lipid II. Gallidermin, which shares the lipid II binding motif with nisin but has a shorter mol. length, differed from nisin in pore formation in several strains of bacteria. To simulate the mode of action, we applied cyclic voltammetry and quartz crystal microbalance to correlate pore formation with lipid II binding kinetics of gallidermin in model membranes. The inability of gallidermin to form pores in DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) (C18/1) and DPoPC (1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine) (C16/1) membranes was related to the membrane thickness. For a better simulation of bacterial membrane characteristics, two different phospholipids with branched fatty acids were incorporated into the DPoPC matrix. Phospholipids with Me branches in the middle of the fatty acid chains favored a lipid II-independent DPoPC permeabilization by gallidermin, while long-branched phospholipids in which the branch is placed near the hydrophilic region induced an identical lipid II-dependent pore formation of gallidermin and nisin. Obviously, the branched lipids altered lipid packing and reduced the membrane thickness. Therefore, the duality of gallidermin activity (pore formation and inhibition of the cell wall synthesis) seems to be balanced by the bacterial membrane compn.
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113. 113
  Muraih, J. K. and Palmer, M. (2012) Estimation of the Subunit Stoichiometry of the Membrane-Associated Daptomycin Oligomer by FRET. Biochim. Biophys. Acta, Biomembr. 1818, 1642– 1647, DOI: 10.1016/j.bbamem.2012.02.019
  113
  Estimation of the subunit stoichiometry of the membrane-associated daptomycin oligomer by FRET
  Muraih, Jawad K.; Palmer, Michael
  Biochimica et Biophysica Acta, Biomembranes (2012), 1818 (7), 1642-1647CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Daptomycin is a lipopeptide antibiotic that kills Gram-pos. bacteria by depolarizing their cell membranes. This antibacterial action of daptomycin is correlated with the formation of membrane-assocd. oligomers. We here examine the no. of subunits contained in one oligomer using fluorescence resonance energy transfer (FRET). The results suggest that the oligomer contains approx. 6-7 subunits, or possibly twice this no. if it spans both membrane monolayers.
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114. 114
  Muraih, J. K., Pearson, A., Silverman, J., and Palmer, M. (2011) Oligomerization of Daptomycin on Membranes. Biochim. Biophys. Acta, Biomembr. 1808, 1154– 1160, DOI: 10.1016/j.bbamem.2011.01.001
  114
  Oligomerization of daptomycin on membranes
  Muraih, Jawad K.; Pearson, Andre; Silverman, Jared; Palmer, Michael
  Biochimica et Biophysica Acta, Biomembranes (2011), 1808 (4), 1154-1160CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Daptomycin (I) is a lipopeptide antibiotic that kills Gram-pos. bacteria by membrane depolarization. While it has long been assumed that the mode of action of I involves the formation of membrane-assocd. oligomers, this has so far not been exptl. demonstrated. Here, the authors used FRET between native I and an NBD-labeled I deriv. to show that such oligomerization indeed occurred. The oligomers were obsd. in the presence of Ca2+ on membrane vesicles isolated from Bacillus subtilis, as well as on model membranes contg. the neg. charged phospholipid, phosphatidylglycerol. In contrast, oligomerization did not occur on membranes contg. phosphatidylcholine only, nor in soln. at micromolar I concns. The requirements for oligomerization of I resembled those previously reported for antibacterial activity, suggesting that oligomerization is necessary for the activity.
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115. 115
  Muraih, J. K., Harris, J., Taylor, S. D., and Palmer, M. (2012) Characterization of Daptomycin Oligomerization with Perylene Excimer Fluorescence: Stoichiometric Binding of Phosphatidylglycerol Triggers Oligomer Formation. Biochim. Biophys. Acta, Biomembr. 1818, 673– 678, DOI: 10.1016/j.bbamem.2011.10.027
  115
  Characterization of daptomycin oligomerization with perylene excimer fluorescence: Stoichiometric binding of phosphatidylglycerol triggers oligomer formation
  Muraih, Jawad K.; Harris, Jesse; Taylor, Scott D.; Palmer, Michael
  Biochimica et Biophysica Acta, Biomembranes (2012), 1818 (3), 673-678CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Daptomycin is a lipopeptide antibiotic that binds to and depolarizes bacterial cell membranes. Its antibacterial activity requires calcium and correlates with the content of phosphatidylglycerol in the target membrane. Daptomycin has been shown to form oligomers on liposome membranes. We here use perylene excimer fluorescence to further characterize the membrane-assocd. oligomer. To this end, the N-terminal fatty acyl chain was replaced with perylene-butanoic acid. The perylene deriv. retains one third of the antibacterial activity of native daptomycin. On liposomes contg. phosphatidylcholine and phosphatidylglycerol, as well as on Bacillus subtilis cells, the perylene-labeled daptomycin forms excimers, which shows that the N-terminal acyl chains of neighboring oligomer subunits are in immediate contact with one another. In a lipid bicelle system, oligomer formation can be titrated with stoichiometric amts. of phosphatidylglycerol. Therefore, the interaction of daptomycin with a single mol. of phosphatidylglycerol is sufficient to trigger daptomycin oligomerization.
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116. 116
  Kreutzberger, M. A., Pokorny, A., and Almeida, P. F. (2017) Daptomycin-Phosphatidylglycerol Domains in Lipid Membranes. Langmuir 33, 13669– 13679, DOI: 10.1021/acs.langmuir.7b01841
  116
  Daptomycin-Phosphatidylglycerol Domains in Lipid Membranes
  Kreutzberger, Mark A.; Pokorny, Antje; Almeida, Paulo F.
  Langmuir (2017), 33 (47), 13669-13679CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
  Daptomycin is an acidic, 13-amino acid, cyclic polypeptide that contains a no. of nonproteinogenic residues and is modified at its N-terminus with a decanoyl chain. It has been in clin. use since 2003 against selected drug-resistant Staphylococcus aureus and Enterococcus spp infections. In vitro, daptomycin is active against Gram-pos. pathogens at low concns. but its antibiotic activity depends critically on the presence of Ca2+ ions. This dependence has been thought to arise from binding of 1 or 2 Ca2+ ions to daptomycin as a required step in its interaction with the bacterial membrane. Here, we investigated the interaction of daptomycin with giant unilamellar vesicles (GUVs) composed 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG). We used fluorescence confocal microscopy to monitor binding of the peptide to GUVs and to follow its effect on the membrane of the vesicle. We found that, in the absence of POPG or Ca2+, daptomycin did not bind measurably to the lipid membrane. In the presence of 20-30% PG in the membrane and 2 mM Ca2+, daptomycin induced the formation of membrane domains rich in acidic lipids. This effect was not induced by Ca2+ alone. In addn., daptomycin caused GUV collapse, but it did not translocate across the membrane to the inside of intact POPC:POPG vesicles. We concluded that pore formation is probably not the mechanism by which the peptide functions. On the other hand, we found that daptomycin coclustered with the anionic phospholipid POPG and the fluorescent probes used, leading to extensive formation of daptomycin-POPG domains in the membrane.
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117. 117
  Domalaon, R., Idowu, T., Zhanel, G. G., and Schweizer, F. (2018) Antibiotic Hybrids: The Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?. Clin. Microbiol. Rev. 31, e00077-17 DOI: 10.1128/CMR.00077-17
  There is no corresponding record for this reference.
118. 118
  Georgopapadakou, N. H., Bertasso, A., Chan, K. K., Chapman, J. S., Cleeland, R., Cummings, L. M., Dix, B. A., and Keith, D. D. (1989) Mode of Action of the Dual-Action Cephalosporin Ro 23–9424. Antimicrob. Agents Chemother. 33, 1067– 1071, DOI: 10.1128/AAC.33.7.1067
  118
  Mode of action of the dual-action cephalosporin Ro 23-9424
  Georgopapadakou, N. H.; Bertasso, A.; Chan, K. K.; Chapman, J. S.; Cleeland, R.; Cummings, L. M.; Dix, B. A.; Keith, D. D.
  Antimicrobial Agents and Chemotherapy (1989), 33 (7), 1067-71CODEN: AMACCQ; ISSN:0066-4804.
  Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biol. properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decompn. product, desacetyl cefotaxime, Ro 23-9424 bound at ≤2 μg/mL to the essential penicillin-bound proteins 1b and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureas. In E. coli, Ro 23-9424 produced filaments exclusively and decreased cell growth; cefotaxime produced both filaments and lysis. Like its decompn. product fleroxacin but unlike quinolone esters, Ro 23-9424 also inhibited replicative DNA biosynthesis in E. coli. In an E. coli strain lacking OmpF, growth continued after addn. of Ro 23-9424, decreased after addn. of cefotaxime, and stopped immediately after addn. of fleroxacin. The results, together with the chem. stability of Ro 23-9424 (half-life, ∼3 h at pH 7.4 and 37°), suggest that in E. coli the compd. acts initially as a cephalosporin with intrinsic activity comparable to that of cefotaxime but with poorer penetration. Subsequent to the decompn. of Ro 23-9424 to fleroxacin and desacetyl cefotaxime, quinolone activity appears. The in vitro antibacterial activity reflects both mechanisms of action.
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119. 119
  Stone, G. W., Zhang, Q., Castillo, R., Doppalapudi, V. R., Bueno, A. R., Lee, J. Y., Li, Q., Sergeeva, M., Khambatta, G., and Georgopapadakou, N. H. (2004) Mechanism of Action of NB2001 and NB2030, Novel Antibacterial Agents Activated by Beta-Lactamases. Antimicrob. Agents Chemother. 48, 477– 483, DOI: 10.1128/AAC.48.2.477-483.2004
  119
  Mechanism of action of NB2001 and NB2030, novel antibacterial agents activated by β-lactamases
  Stone, Geoffrey W.; Zhang, Qin; Castillo, Rosario; Doppalapudi, V. Ramana; Bueno, Analia R.; Lee, Jean Y.; Li, Qing; Sergeeva, Maria; Khambatta, Gody; Georgopapadakou, Nafsika H.
  Antimicrobial Agents and Chemotherapy (2004), 48 (2), 477-483CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compds., NB2001 and NB2030 (I and II, resp.), contain a cephalosporin with a thienyl (I) or a tetrazole (II) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compds. exploit β-lactamases to release triclosan through hydrolysis of the β-lactam ring. Like cephalothin, I and II were hydrolyzed by class A β-lactamases (Escherichia coli TEM-1 and, to a lesser degree, Staphylococcus aureus PC1) and class C β-lactamases (Enterobacter cloacae P99 and E. coli AmpC) with comparable catalytic efficiencies (kcat/Km). They also bound to the penicillin-binding proteins of S. aureus and E. coli, but with reduced affinities relative to that of cephalothin. Accordingly, they produced a cell morphol. in E. coli consistent with the toxophore rather than the β-lactam being responsible for antibacterial activity. In biochem. assays, they inhibited the triclosan target enoyl reductase (FabI), with 50% inhibitory concns. being markedly reduced relative to that of free triclosan. The transport of I and II and triclosan was rapid, with significant accumulation of triclosan in both S. aureus and E. coli. Taken together, the results suggest that I and II act primarily as triclosan prodrugs in S. aureus and E. coli.
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120. 120
  Ma, Z. and Lynch, A. S. (2016) Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections. J. Med. Chem. 59, 6645– 6657, DOI: 10.1021/acs.jmedchem.6b00485
  120
  Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections
  Ma, Zhenkun; Lynch, Anthony Simon
  Journal of Medicinal Chemistry (2016), 59 (14), 6645-6657CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The clin. management of prosthetic joint infections and other persistent bacterial infections represents a major unmet medical need. The rifamycins are one of the most potent antibiotic classes against persistent bacterial infections, but bacteria can develop resistance to rifamycins rapidly and the clin. utility of the rifamycin class is typically limited to antibiotic combinations to minimize the development of resistance. To develop a better therapy against persistent bacterial infections, a series of rifamycin based bifunctional mols. were designed, synthesized, and evaluated with the goal to identify a dual-acting drug that maintains the potent activity of rifamycins against persistent pathogens and at the same time minimize the development of rifamycin resistance. TNP-2092 was identified as a drug candidate and is currently in an early stage of clin. development for the treatment of prosthetic joint infections.
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121. 121
  Gupta, V. and Datta, P. (2019) Next-Generation Strategy for Treating Drug Resistant Bacteria: Antibiotic Hybrids. Indian J. Med. Res. 149, 97– 106, DOI: 10.4103/ijmr.IJMR_755_18
  121
  Next-generation strategy for treating drug resistant bacteria: Antibiotic hybrids
  Gupta, Varsha; Datta, Priya
  Indian Journal of Medical Research (2019), 149 (2), 97-106CODEN: IMIREV ISSN:. (Medknow Publications)
  A review. Resistance against nearly all antibiotics used clin. have been documented in bacteria. There is an ever-increasing danger caused by multidrug-resistant Gram-neg. bacteria in both hospital and community settings. In Gram-neg. bacteria, intrinsic resistance to currently available antibiotics is mainly due to overexpressed efflux pumps which are constitutively present and also presence of protective outer membrane. Combination therapy, i.e., use of two or more antibiotics, was thought to be an effective strategy because it took advantage of the additive effects of multiple antimicrobial mechanisms, lower risk of resistance development and lower mortality and improved clin. outcome. However, none of the benefits were seen in in vivo studies. Antibiotic hybrids are being used to challenge the growing drug resistance threat and increase the usefulness of current antibiotic arsenal. Antibiotic hybrids are synthetic constructs of two mols. which are covalently linked. These could be two antibiotics or antibiotic with an adjuvant (efflux pump inhibitor, siderophore, etc.) which increases the access of the antibiotics to the target. The concepts, developments and challenges in the future use of antibiotic hybrids are discussed here. Majority of the studies have been conducted on fluoroquinolones and aminoglycosides mols. The antibiotic tobramycin has the property to enhance the action of antimicrobial agents against which the multidrug-resistant Gram-neg. bacteria were earlier resistant, and thus potentiating the action of legacy antibiotics. Antibiotic hybrids may have a role as the silver bullet in Gram-neg. bacteria to overcome drug resistance as well as extend the spectrum of existing antibiotics.
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122. 122
  Endres, B. T., Basseres, E., Alam, M. J., and Garey, K. W. (2017) Cadazolid for the Treatment of Clostridium Difficile. Expert Opin. Invest. Drugs 26, 509– 514, DOI: 10.1080/13543784.2017.1304538
  122
  Cadazolid for the treatment of Clostridium difficile
  Endres, Bradley T.; Basseres, Eugenie; Alam, M. Jahangir; Garey, Kevin W.
  Expert Opinion on Investigational Drugs (2017), 26 (4), 509-514CODEN: EOIDER; ISSN:1354-3784. (Taylor & Francis Ltd.)
  Antibiotic development goals for CDI include potent antimicrobial effect against C. difficile, limited killing of host microbiota, potential effect on spores, and ability to interfere with toxin prodn. Cadazolid, a novel, non-absorbable hybrid antibiotic has many of these criteria. In phase I and II clin. trials, cadazolid was shown to be safe, well tolerated, and efficacious positioning itself as a potential future viable therapeutic option for CDI. This review provides an in-depth evaluation of the chem., microbiol., pharmacodynamics, pharmacokinetics, and clin. trial results for cadazolid. Clin. therapeutic outcomes are compared between cadazolid, fidaxomicin, and surotomycin. Preclin. and early clin. studies demonstrated that cadazolid has unique properties that will likely be valuable to treat CDI and reduce recurrent infection. With compelling phase II clin. results, results from the ongoing phase III trial will better define the role of cadazolid for treating CDI in the future.
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123. 123
  Stryjewski, M. E., Potgieter, P. D., Li, Y.-P., Barriere, S. L., Churukian, A., Kingsley, J., and Corey, G. R. (2012) TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections. Antimicrob. Agents Chemother. 56, 5476– 5483, DOI: 10.1128/AAC.00712-12
  123
  TD-1792 versus vancomycin for treatment of complicated skin and skin structure infections
  Stryjewski, Martin E.; Potgieter, Peter D.; Li, Yu-Ping; Barriere, Steven L.; Churukian, Allan; Kingsley, Jeff; Corey, G. Ralph
  Antimicrobial Agents and Chemotherapy (2012), 56 (11), 5476-5483CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  TD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-pos. pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-pos. organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body wt. i.v. [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clin. success at the test-of-cure evaluation were similar in all anal. populations. Among 170 clin. evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, resp. (95% confidence interval [CI] of -7.9 to 9.7 for the difference). In microbiol. evaluable patients with methicillin-resistant Staphylococcus aureus at baseline (n = 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiol. eradication of Gram-pos. pathogens (n = 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, resp. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, resp. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clin. development of TD-1792 in patients with Gram-pos. infection.
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124. 124
  Webb, E. (accessed 2020-03-10) FDA grants QIDP and Fast Track Designations to MCB3837, Morphochem’s novel intravenous antibacterial to treat C. difficile infections, https://www.tvm-lifescience.com/fda-grants-qidp-fast-track-designations-mcb3837-morphochems-novel-intravenous-antibacterial-treat-c-difficile-infections/.
  There is no corresponding record for this reference.
125. 125
  Parkes, A. L. and Yule, I. A. (2016) Hybrid Antibiotics - Clinical Progress and Novel Designs. Expert Opin. Drug Discovery 11, 665– 680, DOI: 10.1080/17460441.2016.1187597
  125
  Hybrid antibiotics - clinical progress and novel designs
  Parkes, Alastair L.; Yule, Ian A.
  Expert Opinion on Drug Discovery (2016), 11 (7), 665-680CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)
  A review. There is a growing need for new antibacterial agents, but success in development of antibiotics in recent years has been limited. This has led researchers to investigate novel approaches to finding compds. that are effective against multi-drug resistant bacteria, and that delay onset of resistance. One such strategy has been to link antibiotics to produce hybrids designed to overcome resistance mechanisms. The concept of dual-acting hybrid antibiotics was introduced and reviewed in this journal in 2010. In the present review the authors sought to discover how clin. candidates described had progressed, and to examine how the field has developed. In three sections the authors cover the clin. progress of hybrid antibiotics, novel agents produced from hybridization of two or more small-mol. antibiotics, and novel agents produced from hybridization of antibiotics with small-mols. that have complementary activity. Many key questions regarding dual-acting hybrid antibiotics remain to be answered, and the proposed benefits of this approach are yet to be demonstrated. While Cadazolid in particular continues to progress in the clinic, suggesting that there is promise in hybridization through covalent linkage, it may be that properties other than antibacterial activity are key when choosing a partner mol.
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126. 126
  Locher, H. H., Seiler, P., Chen, X., Schroeder, S., Pfaff, P., Enderlin, M., Klenk, A., Fournier, E., Hubschwerlen, C., Ritz, D., Kelly, C. P., and Keck, W. (2014) In Vitro and in Vivo Antibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium Difficile Infections. Antimicrob. Agents Chemother. 58, 892– 900, DOI: 10.1128/AAC.01830-13
  126
  In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections
  Locher, Hans H.; Seiler, Peter; Chen, Xinhua; Schroeder, Susanne; Pfaff, Philippe; Enderlin, Michel; Klenk, Axel; Fournier, Elvire; Hubschwerlen, Christian; Ritz, Daniel; Kelly, Ciaran P.; Keck, Wolfgang
  Antimicrobial Agents and Chemotherapy (2014), 58 (2), 892-900, 10 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Clostridium difficile is a leading cause of health care-assocd. diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-assocd. diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clin. development for treatment of CDAD. Here, the authors report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 μg/mL, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics expts., cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concns. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further studies of cadazolid for the treatment of CDAD.
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127. 127
  Locher, H. H., Caspers, P., Bruyère, T., Schroeder, S., Pfaff, P., Knezevic, A., Keck, W., and Ritz, D. (2014) Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium Difficile Infections. Antimicrob. Agents Chemother. 58, 901– 908, DOI: 10.1128/AAC.01831-13
  127
  Investigations of the mode of action and resistance development of cadazolid, a new antibiotic for treatment of Clostridium difficile infections
  Locher, Hans H.; Caspers, Patrick; Bruyere, Thierry; Schroeder, Susanne; Pfaff, Philippe; Knezevic, Andreja; Keck, Wolfgang; Ritz, Daniel
  Antimicrobial Agents and Chemotherapy (2014), 58 (2), 901-908, 9 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Cadazolid is a new oxazolidinone-type antibiotic currently in clin. development for the treatment of Clostridium difficile-assocd. diarrhea. Here, the authors report studies on the mode of action and the propensity for spontaneous resistance development in C. difficile strains. Macromol. labeling expts. indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also obsd., albeit only at substantially higher concns. of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using exts. from different C. difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10-10 at 2× to 4× the MIC), and in multiple-passage expts. (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was obsd., as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.
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128. 128
  Leuthner, K. D., Vidaillac, C., Cheung, C. M., and Rybak, M. J. (2010) In Vitro Activity of the New Multivalent Glycopeptide-Cephalosporin Antibiotic TD-1792 against Vancomycin-Nonsusceptible Staphylococcus Isolates. Antimicrob. Agents Chemother. 54, 3799– 3803, DOI: 10.1128/AAC.00452-10
  128
  In vitro activity of the new multivalent glycopeptide-cephalosporin antibiotic TD-1792 against vancomycin-nonsusceptible Staphylococcus isolates
  Leuthner, Kimberly D.; Vidaillac, Celine; Cheung, Chrissy M.; Rybak, Michael J.
  Antimicrobial Agents and Chemotherapy (2010), 54 (9), 3799-3803CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  TD-1792 is a glycopeptide-cephalosporin heterodimer antibiotic with activity against a broad spectrum of Gram-pos. pathogens that includes methicillin-susceptible and -resistant Staphylococcus aureus. The objective of the present study was to evaluate the in vitro activity of TD-1792 against a collection of clin. isolates of vancomycin-intermediate Staphylococcus spp. (VISS), heteroresistant VISS (hVISS), and vancomycin-resistant S. aureus (VRSA). The TD-1792, vancomycin, daptomycin, linezolid, and quinupristin-dalfopristin MICs and min. bactericidal concns. (MBCs) were detd. for 50 VISS/hVISS isolates and 3 VRSA isolates. Time-kill expts. (TKs) were then performed over 24 h with two vancomycin-intermediate S. aureus strains and two VRSA strains, using each agent at multiples of the MIC. TD-1792 and daptomycin were also evaluated in the presence and absence of 50% human serum to det. the effects of the proteins on their activities. Most of the VISS/hVISS isolates were susceptible to all agents except vancomycin. TD-1792 exhibited the lowest MIC values (MIC90 = 0.125 μg/mL), followed by quinupristin-dalfopristin and daptomycin (MIC90 = 1 μg/mL) and then linezolid (MIC90 = 2 μg/mL). The presence of serum resulted in a 2- to 8-fold increase in the TD-1792 and daptomycin MIC values. In TKs, QD demonstrated bactericidal activity at multiples of the MIC that simulated therapeutic levels, whereas linezolid was only bacteriostatic. Both TD-1792 and daptomycin demonstrated rapid bactericidal activities against all isolates tested. The presence of proteins had only a minimal impact on the activity of TD-1792 in TKs. TD-1792 exhibited significant in vitro activity against multidrug-resistant Staphylococcus isolates and represents a promising candidate for the treatment of infections caused by Gram-pos. organisms.
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129. 129
  Blais, J., Lewis, S. R., Krause, K. M., and Benton, B. M. (2012) Antistaphylococcal Activity of TD-1792, a Multivalent Glycopeptide-Cephalosporin Antibiotic. Antimicrob. Agents Chemother. 56, 1584– 1587, DOI: 10.1128/AAC.05532-11
  129
  Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic
  Blais, Johanne; Lewis, Stacey R.; Krause, Kevin M.; Benton, Bret M.
  Antimicrobial Agents and Chemotherapy (2012), 56 (3), 1584-1587CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  TD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-pos. bacteria. The in vitro activity of TD-1792 was tested against 527 Staphylococcus aureus isolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptible S. aureus (MIC90, 0.015 μg/mL), methicillin-resistant S. aureus, and heterogeneous vancomycin-intermediate S. aureus (MIC90, 0.03 μg/mL). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concns. of ≤0.12 μg/mL. A postantibiotic effect of >2 h was obsd. after exposure to TD-1792.
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130. 130
  Pokrovskaya, V. and Baasov, T. (2010) Dual-Acting Hybrid Antibiotics: A Promising Strategy to Combat Bacterial Resistance. Expert Opin. Drug Discovery 5, 883– 902, DOI: 10.1517/17460441.2010.508069
  130
  Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance
  Pokrovskaya, Varvara; Baasov, Timor
  Expert Opinion on Drug Discovery (2010), 5 (9), 883-902CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)
  A review. Importance of the field: The emerging and sustained resistance to currently available antibiotics and the poor pipeline of new antibacterials urgently call for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell covalently linked into one mol. The possible benefits include: (i) activity against drug-resistant bacteria, (ii) expanded spectrum of activity and (iii) reduced potential for generating bacterial resistance.Areas covered in this review: In this article, we detail the recent activity in the design and development of dual-action hybrid drugs with a non-cleavable linker. We explore newly developed synergistic and antagonistic hybrid compds. with emphases on their potential to reduce resistance development.What the reader will gain: Recently developed synergistic and antagonistic antibacterial drug-drug interactions and the impact of such interactions on the evolution of antibiotic drug resistance are described. Addnl., we discuss the implications of the latter observations on the development of hybrid antibiotics with the emphases on whether their synergistic or antagonistic effect will be more efficient at forestalling/reducing the development of new resistances.Take home message: The approach of dual-acting hybrid antibiotics holds significant current promise in overcoming existing resistance mechanisms, as three of such compds. are entering clin. trials. However, the key challenge in this area should be a broader exptl. demonstration of whether the "synergistic effect" or the "antagonistic effect" of the developed hybrid drug is better at preventing/reducing the evolution of resistance. This fundamental challenge must be overcome before yielding a successful drug.
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131. 131
  Deinove. (accessed 2020-03-10) DNV3837/DNV3681: First-in-class antibiotic candidate, https://www.deinove.com/en/antibiotics/portfolio/dnv3837/dnv3681.
  There is no corresponding record for this reference.
132. 132
  Deinove. (accessed 2020-03-10) An Exploratory, Open-Label, Oligo-Center Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Intravenous DNV3837 in Subjects With Clostridium Difficile Infection, https://clinicaltrials.gov/ct2/show/NCT03988855?term=DNV3681&draw=2&rank=1.
  There is no corresponding record for this reference.
133. 133
  Wang, B., Zhao, Q., Yin, W., Yuan, Y., Wang, X., Wang, Y.-H., Wang, H., Ye, W., Chen, S., Guo, H.-L., and Xie, Y. (2018) In-Vitro Characterisation of a Novel Antimicrobial Agent, TNP-2092, against Helicobacter Pylori Clinical Isolates. Swiss Med. Wkly. 148, w14630 DOI: 10.4414/smw.2018.14630
  133
  In-vitro characterisation of a novel antimicrobial agent, TNP-2092, against Helicobacter pylori clinical isolates
  Ben, Wang; Zhao, Qiaoyun; Yin, Wenzhu; Ying, Yuan; Wang, Xiaomei; Wang, You-Hua; Hui, Wang; Wen, Ye; Chen, Shuping; Guo, Hai-Long; Yong, Xie
  Swiss Medical Weekly (2018), 148 (July), 14630CODEN: SMWWAI; ISSN:1424-7860. (EMH Swiss Medical Publishers Ltd.)
  BACKGROUND AND OBJECTIVES: TNP-2092 is a novel dual-action lead compd. consisting of rifamycin SV and 4H-4-oxo-quinolizine pharmacophores, with a broad spectrum of antibacterial activities. This compd. is currently in the early stage of clin. development for Helicobacter pylori infection. The aim of the present study was to det. the antibacterial activity of TNP-2092 against H. pylori isolated from primary patients. METHODS: A total of 100 H. pylori clin. isolates from primary patients were selected. The min. inhibitory concns. (MICs) for clarithromycin, levofloxacin, rifampin and TNP-2092 were detd. using an agar diln. method. A time-kill study was performed with different concns. of TNP-2092 relevant to MIC against H. pylori ATCC strain 43504 for up to 24 h. The timekill study with drug concns. of 0-4 × MIC was also used to det. the antibacterial activity of TNP-2092 against H. pylori under different pH conditions (pH 4-7). RESULTS: The primary resistance percentages to clarithromycin, levofloxacin, rifampin and TNP-2092 were 13, 18, 1 and 1%, resp. TNP-2092 killing kinetics were both concn. and time dependent. The effectiveness of TNP-2092 against H. pylori was gradually reduced with a decrease in pH. CONCLUSIONS: TNP-2092 is highly active against H. pylori and against strains resistant to clarithromycin or levofloxacin. Its antibacterial activity is both concentrationand time-dependent.The antibacterial activity of TNP-2092 appears to be pH-dependent and is more active under neutral pH. TNP-2092 represents a promising new therapy for the treatment of H. pylori infection in primary patients.
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134. 134
  Burrows, L. L. (2018) The Therapeutic Pipeline for Pseudomonas Aeruginosa Infections. ACS Infect. Dis. 4, 1041– 1047, DOI: 10.1021/acsinfecdis.8b00112
  134
  The Therapeutic Pipeline for Pseudomonas aeruginosa Infections
  Burrows, Lori L.
  ACS Infectious Diseases (2018), 4 (7), 1041-1047CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  Pseudomonas aeruginosa is a Gram-neg. opportunistic pathogen, designated by the World Health Organization as a crit. priority for development of new therapeutics due to high levels of intrinsic and acquired antibiotic resistance. Other challenges include its versatility (it can persist in the environment and most strains are capable of causing disease in compromised hosts), robust efflux mechanisms that limit drug penetration, and the propensity to form antimicrobial-tolerant biofilms. Novel therapeutics in development to prevent or treat P. aeruginosa infections include vaccines, biologics such as antimicrobial peptides and therapeutic antibodies, virulence inhibitors, antimicrobials with novel targets, antibody-drug conjugates, resistance inhibitor-antibiotic or antibiotic-potentiator combinations, and bacteriophages or phage-derived lysins.
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135. 135
  Luther, A., Urfer, M., Zahn, M., Muller, M., Wang, S.-Y., Mondal, M., Vitale, A., Hartmann, J.-B., Sharpe, T., Monte, F. Lo (2019) Chimeric Peptidomimetic Antibiotics against Gram-Negative Bacteria. Nature 576, 452– 458, DOI: 10.1038/s41586-019-1665-6
  135
  Chimeric peptidomimetic antibiotics against Gram-negative bacteria
  Luther, Anatol; Urfer, Matthias; Zahn, Michael; Muller, Maik; Wang, Shuang-Yan; Mondal, Milon; Vitale, Alessandra; Hartmann, Jean-Baptiste; Sharpe, Timothy; Monte, Fabio Lo; Kocherla, Harsha; Cline, Elizabeth; Pessi, Gabriella; Rath, Parthasarathi; Modaresi, Seyed Majed; Chiquet, Petra; Stiegeler, Sarah; Verbree, Carolin; Remus, Tobias; Schmitt, Michel; Kolopp, Caroline; Westwood, Marie-Anne; Desjonqueres, Nicolas; Brabet, Emile; Hell, Sophie; LePoupon, Karen; Vermeulen, Annie; Jaisson, Regis; Rithie, Virginie; Upert, Gregory; Lederer, Alexander; Zbinden, Peter; Wach, Achim; Moehle, Kerstin; Zerbe, Katja; Locher, Hans H.; Bernardini, Francesca; Dale, Glenn E.; Eberl, Leo; Wollscheid, Bernd; Hiller, Sebastian; Robinson, John A.; Obrecht, Daniel
  Nature (London, United Kingdom) (2019), 576 (7787), 452-458CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
  There is an urgent need for new antibiotics against Gram-neg. pathogens that are resistant to carbapenem and 3rd-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. We describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-neg. bacteria. Extensively optimized derivs. show potent activity against multidrug-resistant pathogens, including all of the Gram-neg. members of the ESKAPE pathogens. These derivs. also show favorable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclin. toxicol. studies that, if successful, will allow progress into clin. studies that have the potential to address life-threatening infections by the Gram-neg. pathogens, and thus to resolve a considerable unmet medical need.
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136. 136
  Zhu, Y. I. and Stiller, M. J. (2001) Dapsone and Sulfones in Dermatology: Overview and Update. J. Am. Acad. Dermatol. 45, 420– 434, DOI: 10.1067/mjd.2001.114733
  136
  Dapsone and sulfones in dermatology: overview and update
  Zhu Y I; Stiller M J
  Journal of the American Academy of Dermatology (2001), 45 (3), 420-34 ISSN:0190-9622.
  In their 60-year history, dapsone and the sulfones have been used as both antibacterial and anti-inflammatory agents. Dapsone has been used successfully to treat a range of dermatologic disorders, most successfully those characterized by abnormal neutrophil and eosinophil accumulation. This article reviews and updates the chemistry, pharmacokinetics, clinical application, mechanism of action, adverse effects, and drug interactions of dapsone and the sulfones in dermatology.
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137. 137
  Trivedi, H. D., Lizaola, B., Tapper, E. B., and Bonder, A. (2017) Management of Pruritus in Primary Biliary Cholangitis: A Narrative Review. Am. J. Med. 130, 744.e1– 744.e7, DOI: 10.1016/j.amjmed.2017.01.037
  There is no corresponding record for this reference.
138. 138
  Nakano, T., Hiramatsu, K., Kishi, K., Hirata, N., Kadota, J.-I., and Nasu, M. (2003) Clindamycin Modulates Inflammatory-Cytokine Induction in Lipopolysaccharide-Stimulated Mouse Peritoneal Macrophages. Antimicrob. Agents Chemother. 47, 363– 367, DOI: 10.1128/AAC.47.1.363-367.2003
  138
  Clindamycin modulates inflammatory-cytokine induction in lipopolysaccharide-stimulated mouse peritoneal macrophages
  Nakano, Tetsuji; Hiramatsu, Kazufumi; Kishi, Kenji; Hirata, Norio; Kadota, Jun-Ichi; Nasu, Masaru
  Antimicrobial Agents and Chemotherapy (2003), 47 (1), 363-367CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The authors investigated the mechanism by which clindamycin (CLI) modulates cytokine induction after lipopolysaccharide (LPS) stimulation. Although CLI decreased the intracellular expression levels of tumor necrosis factor α and interleukin 1β (IL-1β) and increased IL-6 expression in macrophages, cytokine mRNA expression levels were similar in CLI-treated and untreated groups. Apparently, CLI modulates cytokine prodn. in LPS-stimulated macrophages.
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139. 139
  van Rensburg, C. E., Gatner, E. M., Imkamp, F. M., and Anderson, R. (1982) Effects of Clofazimine Alone or Combined with Dapsone on Neutrophil and Lymphocyte Functions in Normal Individuals and Patients with Lepromatous Leprosy. Antimicrob. Agents Chemother. 21, 693– 697, DOI: 10.1128/AAC.21.5.693
  139
  Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy
  Van Rensburg, C. E. J.; Gatner, E. M. S.; Imkamp, F. M. J. H.; Anderson, R.
  Antimicrobial Agents and Chemotherapy (1982), 21 (5), 693-7CODEN: AMACCQ; ISSN:0066-4804.
  The effects of clofazimine (I) [2030-63-9] on neutrophil activities such as random motility, migration to the leukoattractants endotoxin-activated serum and N-formyl-L-Met-L-Leu-L-Phe [59880-97-6], phagocytosis of Candida albicans, postphagocytic hexose-monophosphate shunt activity, and myeloperoxidase-mediated iodination and the effects of clofazimine on lymphocyte transformation by mitogens were assessed in vitro and after ingestion of the drug by normal individuals and patients with lepromatous leprosy. For in vitro studies, the concn. range of the drug investigated was 10-6-10-2M. For in vivo studies, subjects ingested 200 mg clofazimine daily for 5 days. At 5 × 10-6M-5 × 10-3M, clofazimine caused a progressive concn.-dependent inhibition of neutrophil motility without detectable effects on phagocytosis, postphagocytic hexose-monophosphate shunt activity, or myeloperoxidase-mediated iodination. Over the same concn. range, clofazimine inhibited lymphocyte transformation. The inhibitory effect on neutrophil motility was assocd. with a spontaneous stimulation of oxidative metab. and could be prevented by coincubation of dapsone [80-08-0] with clofazimine. After ingestion of clofazimine responsiveness of lymphocytes to mitogens was decreased in normal volunteers and leprosy patients; neutrophil motility in normal individuals was likewise inhibited.
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140. 140
  Gatner, E. M., Anderson, R., van Remsburg, C. E., and Imkamp, F. M. (1982) The in Vitro and in Vivo Effects of Clofazimine on the Motility of Neutrophils and Transformation of Lymphocytes from Normal Individuals. Lepr. Rev. 53, 85– 90, DOI: 10.5935/0305-7518.19820010
  140
  The in vitro and in vivo effects of clofazimine on the motility of neutrophils and transformation of lymphocytes from normal individuals
  Gatner, E. M. S.; Anderson, R.; Van Rensburg, C. E.; Imkamp, Florentine M. J. H.
  Leprosy Review (1982), 53 (2), 85-90CODEN: LEREAA; ISSN:0305-7518.
  clofazimine (I) [2030-63-9] caused a progressive dose-dependent inhibition of neutrophil motility and of lymphocyte transformation in vitro. Ingestion of the drug by normal volunteers was accompanied by decreased neutrophil motility and lymphocyte transformation to mitogens. Apparently the anti-inflammatory properties of clofazimine are related to inhibition of these cellular immune functions.
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141. 141
  Zimmermann, P., Ziesenitz, V. C., Curtis, N., and Ritz, N. (2018) The Immunomodulatory Effects of Macrolides—A Systematic Review of the Underlying Mechanisms. Front. Immunol. 9, 302, DOI: 10.3389/fimmu.2018.00302
  141
  The immunomodulatory effects of macrolides-a systematic review of the underlying mechanisms
  Zimmermann, Petra; Ziesenitz, Victoria C.; Curtis, Nigel; Ritz, Nicole
  Frontiers in Immunology (2018), 9 (), 302/1-302/14CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
  Background: The mechanisms underlying the non-antimicrobial immunomodulatory properties of macrolides are not well understood. Objectives: To systematically review the evidence for the immunomodulatory properties of macrolides in humans and to describe the underlying mechanism and extent of their influence on the innate and adaptive immune system. methods: A systematic literature search was done in MEDLINE using the OVID interface from 1946 to Dec. 2016 according to the preferred reporting items for systematic reviews and meta-anal. (PRISMA). Original articles investigating the influence of four macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin) on immuno-logical markers in humans were included. Results: We identified 22 randomized, controlled trials, 16 prospective cohort studies, and 8 case-control studies investigating 47 different immunol. markers (186 mea-surements) in 1,834 participants. The most frequently reported outcomes were a decrease in the no. of neutrophils, and the concns. of neutrophil elastase, interleukin (IL)-8, IL-6, IL-1beta, tumor necrosis factor (TNF)-alpha, eosinophilic cationic protein, and matrix metalloproteinase 9. Inhibition of neutrophil function was reported more frequently than eosinophil function. A decrease in T helper (Th) 2 cells cytokines (IL-4, IL-5, IL-6) was reported more frequently than a decrease in Th1 cytokines (IL-2, INF-gamma). conclusion: Macrolides influence a broad range of immunol. mechanisms result-ing in immunomodulatory effects. To optimize the treatment of chronic inflammatory diseases by macrolides, further studies are necessary, particularly comparing different macrolides and dose effect relationships.
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142. 142
  Pasquale, T. R. and Tan, J. S. (2005) Nonantimicrobial Effects of Antibacterial Agents. Clin. Infect. Dis. 40, 127– 135, DOI: 10.1086/426545
  142
  Nonantimicrobial effects of antibacterial agents
  Pasquale, Timothy R.; Tan, James S.
  Clinical Infectious Diseases (2005), 40 (1), 127-135CODEN: CIDIEL; ISSN:1058-4838. (University of Chicago Press)
  A review. One of the major advances in modern medicine was the development of antimicrobial chemotherapy. However, many antibacterial agents have unexpected or undesirable nonantimicrobial effects on humans. Microbes and man share many essentials of life, including DNA, ATP, and other biochem. pathways. Hence, some of these nonanti- microbial effects may also turn out to be pharmacol. useful. Oral hypoglycemic agents (i.e., sulfonylureas) and a certain diuretic agent (acetazolamide) are derivs. of sulfonamides. Erythromycin has been used clin. for its stimulatory effect on gastrointestinal motility. Macrolides, lincosamides, and tetracyclines have been known for their immunomodulatory effects. A tetracycline has been used to treat the syndrome of inappropriate antidiuretic hormone. Aminoglycosides may influence mucus prodn. in patients with cystic fibrosis. Other antimicrobials may have side effects that are not therapeutically useful, such as osmotic diuresis with high-dose β-lactam administration, neuromuscular blockade of aminoglycosides, dysglycemia of fluoroquinolones, and serotonin syndrome with oxazolidinones.
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143. 143
  Tauber, S. C. and Nau, R. (2008) Immunomodulatory Properties of Antibiotics. Curr. Mol. Pharmacol. 1, 68– 79, DOI: 10.2174/1874467210801010068
  143
  Immunomodulatory properties of antibiotics
  Tauber, S. C.; Nau, R.
  Current Molecular Pharmacology (2008), 1 (1), 68-79CODEN: CMPUB6; ISSN:1874-4672. (Bentham Science Publishers Ltd.)
  A review. There is growing evidence that certain antibiotics exert their beneficial effects not only by killing or inhibiting the growth of bacterial pathogens but also indirectly by immunomodulation. This review aims at giving an overview of the immunomodulatory properties of antibiotics in different diseases: The antiinflammatory properties of macrolides in chronic inflammatory pulmonary disorders were recognized more than 15 years ago and have been well documented in the last decade. Recent data suggest that several antibiotics such as tetracyclines and cephalosporins may have a beneficial immunomodulatory or neuroprotective effect on neuroimmunol. and neurodegenerative diseases including multiple sclerosis and amyotrophic lateral sclerosis. Moreover, the non-bacteriolytic but bactericidal antibiotics rifampicin, clindamycin and aminoglycosides kill bacteria without releasing high quantities of proinflammatory cell wall components. The use of bactericidal, non-bacteriolytic protein synthesis inhibitors reduces mortality and long-term sequelae in exptl. bacterial sepsis, plague and meningitis. Clin., macrolides have been well established as an adjunctive treatment to β-lactam antibiotics in pulmonary diseases. For other indications, appropriate clin. trials are necessary before using the immunomodulatory properties of antibiotics in clin. practice.
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144. 144
  Ye, Y., Xia, Z., Zhang, D., Sheng, Z., Zhang, P., Zhu, H., Xu, N., and Liang, S. (2019) Multifunctional Pharmaceutical Effects of the Antibiotic Daptomycin. BioMed Res. Int. 2019, 8609218, DOI: 10.1155/2019/8609218
  144
  Multifunctional Pharmaceutical Effects of the Antibiotic Daptomycin
  Ye Yang; Zhang Dan; Sheng Zenghua; Xu Ningzhi; Liang Shufang; Xia Zijing; Zhang Peng; Zhu Hongxia; Xu Ningzhi
  BioMed research international (2019), 2019 (), 8609218 ISSN:.
  Daptomycin (DAP), a cyclic lipopeptide produced by Streptomyces roseosporus, is a novel antibiotic to clinically treat various Gram-positive pathogenic bacteria-induced infections. Although DAP has a strong broad-spectrum bactericidal effect, recently rare bacterial antibiotic resistance against DAP gradually arises. The review is to summarize the normal indications of DAP, its off-label usage against several clinical pathogen infections, the unique antibacterial mechanisms of DAP, and the combination of antibiotic therapies for highly DAP-resistant pathogens. More noticeably, rising evidences demonstrate that DAP has new potential activity of anticancer and immunomodulatory effects. So far the multifunctional pharmaceutical effects of DAP deserve to be further explored for future clinical applications.
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145. 145
  Jorgensen, S. C. J., Zasowski, E. J., Trinh, T. D., Lagnf, A. M., Bhatia, S., Sabagha, N., Abdul-Mutakabbir, J. C., Alosaimy, S., Mynatt, R. P., Davis, S. L., and Rybak, M. J. (2019) Daptomycin plus Beta-Lactam Combination Therapy for Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections: A Retrospective, Comparative Cohort Study. Clin. Infect. Dis. ciz746 DOI: 10.1093/cid/ciz746
  There is no corresponding record for this reference.
146. 146
  Meletiadis, J., Petraitis, V., Petraitiene, R., Lin, P., Stergiopoulou, T., Kelaher, A. M., Sein, T., Schaufele, R. L., Bacher, J., and Walsh, T. J. (2006) Triazole-Polyene Antagonism in Experimental Invasive Pulmonary Aspergillosis: In Vitro and in Vivo Correlation. J. Infect. Dis. 194, 1008– 1018, DOI: 10.1086/506617
  146
  Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo correlation
  Meletiadis, Joseph; Petraitis, Vidmantas; Petraitiene, Ruta; Lin, Pengxin; Stergiopoulou, Theodouli; Kelaher, Amy M.; Sein, Tin; Schaufele, Robert L.; Bacher, John; Walsh, Thomas J.
  Journal of Infectious Diseases (2006), 194 (7), 1008-1018CODEN: JIDIAQ; ISSN:0022-1899. (University of Chicago Press)
  Combination antifungal therapy is increasingly used in the treatment of invasive aspergillosis. Whether the interaction between amphotericin B and triazoles is antagonistic against invasive aspergillosis is a controversial issue that is not likely to be resolved through a randomized clin. trial. Here, we found both in vitro and in vivo antagonism between liposomal amphotericin B and ravuconazole in simultaneous treatment of exptl. invasive pulmonary aspergillosis in persistently neutropenic rabbits. Bliss independence-based drug-interaction modeling showed significant antagonism in vitro and in vivo, with the obsd. drug effects being 20%-69% lower than would be expected if the drugs were acting independently. These in vitro and in vivo findings of antagonism were consistent with the findings from Loewe additivity-based drug-interaction modeling. No pharmacokinetic interaction was found. The combination of a triazole and polyene may be antagonistic in the treatment of invasive pulmonary aspergillosis.
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147. 147
  Gonzalez-Bello, C. (2017) Antibiotic Adjuvants - A Strategy to Unlock Bacterial Resistance to Antibiotics. Bioorg. Med. Chem. Lett. 27, 4221– 4228, DOI: 10.1016/j.bmcl.2017.08.027
  147
  Antibiotic adjuvants - A strategy to unlock bacterial resistance to antibiotics
  Gonzalez-Bello, Concepcion
  Bioorganic & Medicinal Chemistry Letters (2017), 27 (18), 4221-4228CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the no. of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has spread worldwide. To unlock this problem, the use of an 'antibiotic adjuvant' in combination with an antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those compds. that are already in clin. development, namely β-lactamase inhibitors.
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148. 148
  Kwapong, A. A., Stapleton, P., and Gibbons, S. (2019) Inhibiting Plasmid Mobility: The Effect of Isothiocyanates on Bacterial Conjugation. Int. J. Antimicrob. Agents 53, 629– 636, DOI: 10.1016/j.ijantimicag.2019.01.011
  148
  Inhibiting plasmid mobility: The effect of isothiocyanates on bacterial conjugation
  Kwapong, Awo Afi; Stapleton, Paul; Gibbons, Simon
  International Journal of Antimicrobial Agents (2019), 53 (5), 629-636CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
  Bacterial conjugation is the main mechanism for the transfer of multiple antimicrobial resistance genes among pathogenic microorganisms. This process may be controlled by compds. that inhibit bacterial conjugation. The effects of allyl isothiocyanate, L-sulforaphane, benzyl isothiocyanate, phenylethyl isothiocyanate, and 4-methoxyphenyl isothiocyanate on the conjugation of broad-host-range plasmids harboring various antimicrobial resistance genes in Escherichia coli were investigated, namely plasmids pKM101 (IncN), TP114 (IncI2), pUB307 (IncP), and the low-copy-no. plasmid R7K (IncW). Benzyl isothiocyanate (32 mg/L) significantly reduced conjugal transfer of pKM101, TP114, and pUB307 to 0.3%, 10.7%, and 6.5%, resp.; L-sulforaphane (16 mg/L; transfer frequency 21.5%); and 4-methoxyphenyl isothiocyanate (100 mg/L; transfer frequency 5.2%) were the only compds. showing anti-conjugal specificity by actively reducing the transfer of R7K and pUB307, resp.
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149. 149
  Zhao, W. H., Hu, Z. Q., Okubo, S., Hara, Y., and Shimamura, T. (2001) Mechanism of Synergy between Epigallocatechin Gallate and Beta-Lactams against Methicillin-Resistant Staphylococcus Aureus. Antimicrob. Agents Chemother. 45, 1737– 1742, DOI: 10.1128/AAC.45.6.1737-1742.2001
  149
  Mechanism of synergy between epigallocatechin gallate and β-lactams against methicillin-resistant Staphylococcus aureus
  Zhao, Wei-Hua; Hu, Zhi-Qing; Okubo, Sachie; Hara, Yukihiko; Shimamura, Tadakatsu
  Antimicrobial Agents and Chemotherapy (2001), 45 (6), 1737-1742CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  Compared to MICs (>800 μg/mL) of (-)-epigallocatechin gallate (I) against Escherichia coli, MICs of I against methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA) were ≤100 μg/mL. Furthermore, <25 μg I/mL obviously reversed the high level resistance of MRSA to all types of tested β-lactams, including benzylpenicillin, oxacillin, methicillin, ampicillin, and cephalexin. I also induced a supersusceptibility to β-lactams in MSSA which does not express mecA, encoding penicillin-binding protein 2' (PBP2'). The fractional inhibitory concn. (FIC) indexes of the tested β-lactams against 25 isolates of MRSA were 0.126-0.625 in combination with 6.25, 12.5, or 25 μg I/mL. However, no synergism was obsd. between I and ampicillin against E. coli. I largely reduced the tolerance of MRSA and MSSA to high ionic strength and low osmotic pressure in their external atm., indicating damage of the cell wall. Unlike dextran and lipopolysaccharide, peptidoglycan from S. aureus blocked both the antibacterial activity of I and the synergism between I and oxacillin, suggesting a direct binding of I with peptidoglycan on the cell wall. I showed a synergistic effect with DL-cycloserine (an inhibitor of cell wall synthesis unrelated to PBP2') but additive or indifferent effect with inhibitors of protein and nuclear acid synthesis. I did not suppress either PBP2' mRNA expression or PBP2' prodn., as confirmed by reverse transcription-PCR and a semiquant. PBP2' latex agglutination assay, indicating an irrelevance between the synergy and PBP2' prodn. In summary, both I and β-lactams directly or indirectly attack the same site, peptidoglycan on the cell wall. I synergizes the activity of β-lactams against MRSA owing to interference with the integrity of the cell wall through direct binding to peptidoglycan.
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150. 150
  Rand, K. H. and Houck, H. (2004) Daptomycin Synergy with Rifampicin and Ampicillin against Vancomycin-Resistant Enterococci. J. Antimicrob. Chemother. 53, 530– 532, DOI: 10.1093/jac/dkh104
  150
  Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci
  Rand, Kenneth H.; Houck, Herbert
  Journal of Antimicrobial Chemotherapy (2004), 53 (3), 530-532CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  The authors used a novel screening method to look for synergy between daptomycin and 18 other antibiotics against 19 strains of high-level vancomycin-resistant enterococci (VRE) (vancomycin MIC ≥ 256 mg/L). In this approach, daptomycin was incorporated into Ca2+-supplemented Mueller-Hinton agar at subinhibitory concns., and synergy was screened by comparing test antibiotic Etest MICs on agar with and without daptomycin. A striking redn. in the rifampicin MIC was seen in 11/15 (73.3%) VRE that were resistant to rifampicin, from ≥12 mg/L to a mean ± s.d. of 0.22 ± 0.21 mg/L at daptomycin 0.25 × MIC and 0.85 ± 0.90 mg/L at daptomycin 0.125 × MIC. Synergy was also obsd. for 13/19 (68%) isolates with ampicillin (MIC ≥ 128 mg/L). There was no significant synergy between daptomycin and any other antibiotic by this screening method. If confirmed by further studies, daptomycin with either rifampicin or ampicillin may be useful in the management of infections caused by VRE.
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151. 151
  Paul, T. R., Venter, A., Blaszczak, L. C., Parr, T. R. J., Labischinski, H., and Beveridge, T. J. (1995) Localization of Penicillin-Binding Proteins to the Splitting System of Staphylococcus Aureus Septa by Using a Mercury-Penicillin V Derivative. J. Bacteriol. 177, 3631– 3640, DOI: 10.1128/JB.177.13.3631-3640.1995
  151
  Localization of penicillin-binding proteins to the splitting system of Staphylococcus aureus septa by using a mercury-penicillin V derivative
  Paul, Terry R.; Venter, Alexandra; Blaszczak, Larry C.; Parr, Tom R., Jr.; Labischinski, Harald; Beveridge, Terry J.
  Journal of Bacteriology (1995), 177 (13), 3631-40CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
  Precise localization of penicillin-binding protein (PBP)-antibiotic complexes in a methicillin-sensitive Staphylococcus aureus strain (BB255), its isogenic heterogeneous methicillin-resistant transductant (BB270), and a homogeneous methicillin-resistant strain (Col) was investigated by high-resoln. electron microscopy. A mercury-penicillin V (Hg-pen V) deriv. was used as a heavy metal-labeled, electron-dense probe for accurately localizing PBPs in situ in single bacterial cells during growth. The most striking feature of thin sections was the presence of an abnormally large (17 to 24 nm in width) splitting system within the thick cross walls or septa of Hg-pen V-treated bacteria of all strains. Untreated control cells possessed a thin, condensed splitting system, 7 to 9 nm in width. A thick splitting system was also distinguishable in unstained thin sections, thereby confirming that the electron contrast of this structure was not attributed to binding of bulky heavy metal stains usually used for electron microscopy. Biochem. analyses demonstrated that Hg-pen V bound to isolated plasma membranes as well as sodium dodecyl sulfate-treated cell walls and that two or more PBPs in each strain bound to this antibiotic. In contrast, the splitting system in penicillin V-treated bacteria was rarely visible after 30 min in the presence of antibiotic. These findings suggest that while most PBPs were assocd. with the plasma membrane, a proportion of PBPs were located within the fabric of the cell wall, in particular, in the splitting system. Inhibition of one or more high-Mr PBPs by β-lactam antibiotics modified the splitting system and cross-wall structure, therefore supporting a role for these PBPs in the synthesis and architectural design of these structures in S. aureus.
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152. 152
  Biebricher, C. K. and Druminski, M. (1980) Inhibition of RNA Polymerase Activity by the Escherichia Coli Protein Biosynthesis Elongation Factor Ts. Proc. Natl. Acad. Sci. U. S. A. 77, 866– 869, DOI: 10.1073/pnas.77.2.866
  152
  Inhibition of RNA polymerase activity by the Escherichia coli protein biosynthesis elongation factor Ts
  Biebricher, Christof K.; Druminski, Maria
  Proceedings of the National Academy of Sciences of the United States of America (1980), 77 (2), 866-9CODEN: PNASA6; ISSN:0027-8424.
  The transcribing activity of DNA-dependent RNA polymerase (EC 2.7.7.6) from E. coli was inhibited in vitro by addn. of prepns. of elongation factor Ts purified to homogeneity. The inhibitory activity of elongation factor Ts on RNA polymerase activity and the enzymic activity of elongation factor Ts showed the same temp. sensitivity. The extent of inhibition was strongly dependent on the template used for transcription. A mechanism for the control of RNA synthesis in vivo based on this inhibition found in vitro is proposed.
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153. 153
  Nasher, M. A. and Hay, R. J. (1998) Synergy of Antibiotics against Streptomyces Somaliensis Isolates in Vitro. J. Antimicrob. Chemother. 41, 281– 284, DOI: 10.1093/jac/41.2.281
  153
  Synergy of antibiotics against Streptomyces somaliensis isolates in vitro
  Nasher, M. A.; Hay, R. J.
  Journal of Antimicrobial Chemotherapy (1998), 41 (2), 281-284CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  Eight dual antibiotic combinations were used to investigate possible synergic effects against different isolates of Streptomyces somaliensis. The antibiotic combinations that showed synergic activity against the isolates were, in decreasing order, fusidic acid-rifampicin, erythromycin-penicillin, erythromycin-fusidic acid, rifampicin-sulphamethoxazole, fusidic acid-sulphamethoxazole and erythromycin-rifampicin. Sulphamethoxazole-trimethoprim and rifampicin-trimethoprim combinations were not synergic against any of the S. somaliensis isolates tested.
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154. 154
  Lowe, P. A. and Malcolm, A. D. (1976) Rifampicin Binding as a Probe for Subunit Interactions in Escherchia Coli RNA Polymerase. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 454, 129– 137, DOI: 10.1016/0005-2787(76)90360-9
  154
  Rifampicin binding as a probe for subunit interactions in Escherichia coli RNA polymerase
  Lowe, Peter A.; Malcolm, Alan D. B.
  Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1976), 454 (1), 129-37CODEN: BBNPAS; ISSN:0005-2787.
  The binding of the inhibitor rifampicin to RNA polymerase(α2ββ1) and its deficient subunit mixts. was investigated. The ability of β to bind stoichiometric amts. of rifampicin was restored by formation of the α2β subassembly. β,β1α, ββ1, And α2β1 were unable to bind rifampicin. RNA polymerase denatured with 6M guanidine-HCl and dialyzed against a renaturing buffer at 0° (renatured inactive enzyme) bound stoichiometric amts. of rifampicin but lost the ability to bind DNA. Compared with native RNA polymerase renatured inactive enzyme possessed a markedly different tertiary structure as judged by limited proteolysis.
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155. 155
  Lee-Huang, S., Lee, H., and Ochoa, S. (1974) Inhibition of Polypeptide Chain Initiation in Escherichia Coli by Elongation Factor G. Proc. Natl. Acad. Sci. U. S. A. 71, 2928– 2931, DOI: 10.1073/pnas.71.8.2928
  155
  Inhibition of polypeptide chain initiation in Escherichia coli by elongation factor G
  Lee-Huang, Sylvia; Lee, Henry; Ochoa, Severo
  Proceedings of the National Academy of Sciences of the United States of America (1974), 71 (8), 2928-31CODEN: PNASA6; ISSN:0027-8424.
  A specific inhibitor of polypeptide chain initiation from E. coli is rendered ineffective when active aminoacylation of transfer RNA is taking place (Lee-Huang, S., et al., 1973). The inhibitory activity appeared to be a hitherto unrecognized property of the chain elongation factor G. The following hold for prepns. purified for either translocase or inhibitor activity: (1) equal electrophoretic mobility on polyacrylamide gels; (2)equal sp. activities for inhibition of initiation, translocation, and ribosome-dependent, uncoupled GTPase; and (3) similar heat sensitivity of translocase and inhibitor activities in a temp.-sensitive E. coli mutant with an altered elongation factor G. Different sites are apparently involved in translocation and inhibition because the former, but not the latter, is sensitive to p-chloromercuribenzoate and fusidic acid.
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156. 156
  Dinos, G. P., Connell, S. R., Nierhaus, K. H., and Kalpaxis, D. L. (2003) Erythromycin, Roxithromycin, and Clarithromycin: Use of Slow-Binding Kinetics to Compare Their in Vitro Interaction with a Bacterial Ribosomal Complex Active in Peptide Bond Formation. Mol. Pharmacol. 63, 617– 623, DOI: 10.1124/mol.63.3.617
  156
  Erythromycin, roxithromycin, and clarithromycin: Use of slow-binding kinetics to compare their in vitro interaction with a bacterial ribosomal complex active in peptide bond formation
  Dinos, George P.; Connell, Sean R.; Nierhaus, Knud H.; Kalpaxis, Dimitrios L.
  Molecular Pharmacology (2003), 63 (3), 617-623CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)
  In a cell-free system derived from Escherichia coli, it is shown that clarithromycin and roxithromycin, like their parent compd. erythromycin, do not inhibit the puromycin reaction (i.e., the peptide bond formation between puromycin and AcPhe-tRNA bound at the P-site of 70S ribosomes programmed with heteropolymeric mRNA). Nevertheless, all three antibiotics compete for binding on the ribosome with tylosin, a 16-membered ring macrolide that behaves as a slow-binding, slowly reversible inhibitor of peptidyltransferase. The mutually exclusive binding of these macrolides to ribosomes is also corroborated by the fact that they protect overlapping sites in domain V of 23S rRNA from chem. modification by di-Me sulfate. From this competition effect, detailed kinetic anal. revealed that roxithromycin or clarithromycin (A), like erythromycin, reacts rapidly with AcPhe-tRNA·MF-mRNA·70S ribosomal complex (C) to form the encounter complex CA which is then slowly isomerized to a more tight complex, termed C*A. MF-mRNA is a heteropolymeric synthetic mRNA used as template in place of poly(U). It is 46-nucleotides long with an AUG codon in the middle, followed by a UUC codon. The value of the overall dissocn. const., K*A, encompassing both steps of macrolide interaction with complex C, is 36 nM for erythromycin, 20 nM for roxithromycin, and 8 nM for clarithromycin. Because the off-rate const. of C*A complex does not significantly differ among the three macrolides, the superiority of clarithromycin as an inhibitor of translation in E. coli cells and many Gram-pos. bacteria may be correlated with its greater rate of assocn. with ribosomes.
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157. 157
  Allen, N. E. and Epp, J. K. (1978) Mechanism of Penicillin-Erythromycin Synergy on Antibiotic-Resistant Staphylococcus Aureus. Antimicrob. Agents Chemother. 13, 849– 853, DOI: 10.1128/AAC.13.5.849
  157
  Mechanism of penicillin-erythromycin synergy on antibiotic-resistant Staphylococcus aureus
  Allen, Norris E.; Epp, Janet K.
  Antimicrobial Agents and Chemotherapy (1978), 13 (5), 849-53CODEN: AMACCQ; ISSN:0066-4804.
  Clin. isolated strains of S. aureus that are inducibly resistant to both erythromycin [114-07-8] and benzylpenicillin [61-33-6] were susceptible to a combination of the 2 antibiotics. The synergistic effect of the combination results from an inhibition of penicillinase [9001-74-5] induction by erythromycin, sparing penicillin and allowing this drug to inhibit growth. When resistance to erythromycin was constitutive rather than inducible, the combination was no longer synergistic.
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158. 158
  Guignard, B., Entenza, J. M., and Moreillon, P. (2005) Beta-Lactams against Methicillin-Resistant Staphylococcus Aureus. Curr. Opin. Pharmacol. 5, 479– 489, DOI: 10.1016/j.coph.2005.06.002
  158
  β-lactams against methicillin-resistant Staphylococcus aureus
  Guignard, Bertrand; Entenza, Jose M.; Moreillon, Philippe
  Current Opinion in Pharmacology (2005), 5 (5), 479-489CODEN: COPUBK; ISSN:1471-4892. (Elsevier Ltd.)
  A review. Methicillin-resistant Staphylococcus aureus (MRSA) have developed resistance to virtually all non-exptl. antibiotics. They are intrinsically resistant to β-lactams by virtue of newly acquired low-affinity penicillin-binding protein 2A (PBP2A). Because PBP2A can build the wall when other PBPs are blocked by β-lactams, designing β-lactams capable of blocking this addnl. target should help solve the issue. Older mols. including penicillin G, amoxicillin and ampicillin had relatively good PBP2A affinities, and successfully treated exptl. endocarditis caused by MRSA, provided that the bacterial penicillinase could be inhibited. Newer anti-PBP2A β-lactams with over 10-fold greater PBP2A affinities and low minimal inhibitory concns. were developed, primarily in the cephem and carbapenem classes. They are also very resistant to penicillinase. Most have demonstrated anti-MRSA activity in animal models of infection, and two - the carbapenem CS-023 and the cephalosporin ceftopibrole medocaril - have proceeded to Phase II and Phase III clin. evaluation. Thus, clin. useful anti-MRSA β-lactams are imminent.
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159. 159
  Brandt, C. M., Rouse, M. S., Laue, N. W., Stratton, C. W., Wilson, W. R., and Steckelberg, J. M. (1996) Effective Treatment of Multidrug-Resistant Enterococcal Experimental Endocarditis with Combinations of Cell Wall-Active Agents. J. Infect. Dis. 173, 909– 913, DOI: 10.1093/infdis/173.4.909
  159
  Effective treatment of multidrug-resistant enterococcal experimental endocarditis with combinations of cell wall-active agents
  Brandt, Claudia M.; Rouse, Mark S.; Laue, Natasha W.; Stratton, Charles W.; Wilson, Walter R.; Steckelberg, James M.
  Journal of Infectious Diseases (1996), 173 (4), 909-13CODEN: JIDIAQ; ISSN:0022-1899. (University of Chicago Press)
  The efficacy of treatment with a combination of ampicillin, imipenem, and vancomycin was compared with that of two-drug combinations or monotherapy in a model of exptl. endocarditis using a strain of Enterococcus faecium with high-level resistance to vancomycin and moderate intrinsic resistance to ampicillin and imipenem. In vitro time-kill synergy studies demonstrated bactericidal synergistic activity only for the triple combination. In vivo, monotherapy with vancomycin was not effective. Treatment with either ampicillin or imipenem alone or in combination with vancomycin resulted in <4 log10 redn. in colony-forming units (cfu) per g of vegetation. The combination of ampicillin with imipenem was highly active (an addnl. 5 log10 redn. in cfu per g of vegetation compared with the most active single agent), but efficacy was not increased by the addn. of vancomycin to ampicillin and imipenem. Therapy with the combination of ampicillin and imipenem may be effective for some strains of multidrug-resistant enterococcal infections.
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160. 160
  Drew, R. H. and Gallis, H. A. (1992) Azithromycin--Spectrum of Activity, Pharmacokinetics, and Clinical Applications. Pharmacotherapy 12, 161– 173, DOI: 10.1002/j.1875-9114.1992.tb04504.x
  160
  Azithromycin--spectrum of activity, pharmacokinetics, and clinical applications
  Drew R H; Gallis H A
  Pharmacotherapy (1992), 12 (3), 161-73 ISSN:0277-0008.
  Azithromycin is an azalide antimicrobial agent. Structurally related to the macrolide antibiotic erythromycin, its mechanism of activity (similar to erythromycin) is interference with bacterial protein synthesis by binding to the 50S component of the 70S ribosomal subunit. Although slightly less potent than erythromycin against gram-positive organisms, azithromycin demonstrates superior activity in vitro against a wide variety of gram-negative bacilli, including Haemophilus influenzae. Absorption is approximately 37% after a 500-mg oral dose. The large volume of distribution (23 L/kg) and low peak serum level (0.4 micrograms/ml) are consistent with data demonstrating extensive tissue distribution and intracellular accumulation. Metabolism is predominantly hepatic (to inactive metabolites), with biliary excretion a major pathway of elimination. Drug elimination is biphasic, with a terminal half-life of up to 5 days. Published trials have examined the efficacy and safety of azithromycin in the treatment of adults with upper and lower respiratory tract infections, skin and skin structure infections, streptococcal pharyngitis, and sexually transmitted diseases. Many used a 5-day course of 250 mg once daily, supplemented with a 250-mg dose on the first day of therapy. Selected trials in sexually transmitted diseases examined single 1-g doses. Promising results also were obtained with oral daily doses of 500 mg in patients with human immunoviral infection who also had Mycobacterium avium complex infection and in animals with toxoplasmosis. Adverse reactions are primarily gastrointestinal (nausea, diarrhea, abdominal pain), with minimal laboratory abnormalities reported. Gastrointestinal tolerance is better than that of erythromycin. Drug interactions have not been observed to date, although coadministration of azithromycin with a large meal may reduce absorption by up to 50%.
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161. 161
  Ono, S., Muratani, T., and Matsumoto, T. (2005) Mechanisms of Resistance to Imipenem and Ampicillin in Enterococcus Faecalis. Antimicrob. Agents Chemother. 49, 2954– 2958, DOI: 10.1128/AAC.49.7.2954-2958.2005
  161
  Mechanisms of resistance to imipenem and ampicillin in Enterococcus faecalis
  Ono, Seiji; Muratani, Tetsuro; Matsumoto, Tetsuro
  Antimicrobial Agents and Chemotherapy (2005), 49 (7), 2954-2958CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  We found ampicillin- and imipenem-resistant isolates of vanA-possessing Enterococcus faecalis with MICs of 8 to 16 μg/mL and 4 to 32 μg/mL, resp. There have been few reports about penicillin- and imipenem-resistant E. faecalis. Two mechanisms of beta-lactam resistance in E. faecalis, the prodn. of beta-lactamase and the overprodn. of penicillin-binding proteins (PBPs), have been reported. The resistant isolates in the current study did not produce any beta-lactamases and anal. of the PBPs showed no overprodn. However, the affinities of PBP4 for beta-lactams in the resistant strains were lower than those of susceptible strains but the affinities of other PBPs for beta-lactams did not change. Accordingly, whole pbp4 fragments from these resistant isolates were sequenced. Two amino acid substitutions at positions 520 and 605 were obsd. in the highly resistant strains compared to the susceptible ones, Pro520Ser and Tyr605His, and a single Tyr605His amino acid substitution was found in the low-resistance strains. These two point mutations exist in the region between the active-site-defining motifs SDN and KTG of the penicillin-binding domain, the main target of beta-lactams. A strong correlation was seen between these substitutions and decreasing affinities of PBP4 to beta-lactams. In E. faecalis, resistance due to mutations in PBPs has not been reported, though it has in Enterococcus faecium. Our results suggest that development of high-level resistance to penicillins and imipenem depends on point mutations of PBP4 at positions 520 and 605.
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162. 162
  Brumfitt, W. and Hamilton-Miller, J. M. (1993) Reassessment of the Rationale for the Combinations of Sulphonamides with Diaminopyrimidines. J. Chemother. 5, 465– 469, DOI: 10.1080/1120009X.1993.11741097
  162
  Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines
  Brumfitt W; Hamilton-Miller J M
  Journal of chemotherapy (Florence, Italy) (1993), 5 (6), 465-9 ISSN:1120-009X.
  Trimethoprim is the best known inhibitor of bacterial dihydrofolate reductase. Initially, this was always combined with sulphamethoxazole. It was later combined with other sulphonamides (eg. sulphamoxole, sulphadiazine or sulfametopyrazine), but the sulphonamide moiety as a contributor to clinical efficacy was increasingly questioned. Thus, in 1979 (in UK) trimethoprim alone was introduced. Justification for the combination was based on: (a) synergy occurs in vitro (b) bactericidal activity, while the two components are bacteriostatic (c) the emergence of resistance was claimed to be lower. However, these claims were not substantiated by studying the microbiological and pharmacokinetic properties of trimethoprim and the sulphonamides, but most importantly by the results of clinical trials. These show that in most indications, trimethoprim alone is as good, cheaper and causes considerably fewer adverse events than use with a sulphonamide. For urinary infections most agree that monotherapy is best. In respiratory infections diaminopyrimidines have relatively poor activity against important pathogens, eg pneumococci and especially Moraxella catarrhalis. It could be argued in these case that the addition of a sulphonamide may increase therapeutic efficacy. This can only be resolved by large clinical trials. In brucellosis and gonorrhoea, where sulphonamides are more microbiologically active than diaminopyrimidines, it is likely that combination with another antibiotic is needed. However, too much reliance must not be placed on extrapolating from trimethoprim to other diaminopyrimidines; conclusions should be drawn from work using the other compounds.
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163. 163
  Voeller, D., Kovacs, J., Andrawis, V., Chu, E., Masur, H., and Allegra, C. (1994) Interaction of Pneumocystis Carinii Dihydropteroate Synthase with Sulfonamides and Diaminodiphenyl Sulfone (Dapsone). J. Infect. Dis. 169, 456– 459, DOI: 10.1093/infdis/169.2.456
  163
  interaction of Pneumocystis carinii dihydropteroate synthase with sulfonamides and diaminodiphenyl sulfone (Dapsone)
  Voeller, Donna; Kovacs, Joseph; Andrawis, Vivian; Chu, Edward; Masur, Henry; Allegra, Carmen
  Journal of Infectious Diseases (1994), 169 (2), 456-9CODEN: JIDIAQ; ISSN:0022-1899.
  Dihydropteroate synthase is the target enzyme for the sulfonamide compds., which are the mainstay of therapy for Pneumocystis carinii pneumonia, a common infection in patients with impaired immunity. The stability of this enzyme, its kinetic consts. with respect to substrates, and the 50% inhibitory concn. (IC50) of several sulfonamides and the sulfone dapsone have been characterized using both cell-free and intact organism assay systems. Stability of the enzyme is dependent on storage temp., reducing reagents, and to a lesser extent, protease inhibitors. The sulfonamides sulfadiazine and sulfamethoxazole were highly potent inhibitors of P. carinii dihydropteroate synthase with IC50s of 0.42 and 0.71 μM, resp. Dapsone had equiv. potency when compared with the most potent sulfonamides tested in both assay systems. Data suggest that sulfamethoxazole, sulfadiazine, and dapsone may represent equiv. choices as P. carinii dihydropteroate synthase inhibitors, assuming an equiv. in vivo drug exposure can be achieved.
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164. 164
  Greenwood, D. and O’Grady, F. (1976) Activity and Interaction of Trimethoprim and Sulphamethoxazole against Escherichia Coli. J. Clin. Pathol. 29, 162– 166, DOI: 10.1136/jcp.29.2.162
  164
  Activity and interaction of trimethoprim and sulfamethoxazole against Escherichia coli
  Greenwood, D.; O'Grady, F.
  Journal of Clinical Pathology (1976), 29 (2), 162-6CODEN: JCPAAK; ISSN:0021-9746.
  Studies of the activity of trimethoprim lactate (I lactate) [23256-42-0] and sulfamethoxazole (II) [723-46-6] alone and in combination [8064-90-2] against a sensitive strain of Escherichia coli showed that in a static system in which the conditions of exposure of bacteria to drug resembled those of conventional min. inhibitory concn. (MIC) titrns., both I and II exhibited antibacterial activity at concns. well below the conventionally detd. MIC, but regrowth occurred at these concns. during the overnight incubation period due to the emergence of adaptively resistant bacteria. Tests of combined drug action in the static turbidimetric system revealed even more synergic interaction than was apparent in conventional MIC tests, suggesting that an important component of overall synergic interaction is the mutual suppression of adaptive resistance to the other agent. Studies in an in vitro model which simulates the hydrokinetic features of the urinary bladder showed that concns. of I and II below the conventionally detd. MIC inhibited the growth even of extremely dense bacterial populations so long as the concn. of drug was maintained. The response of cultures exposed to combinations of I and II in this system was so dominated by the effect of I that no synergic interaction with II was noted at concns. of the drugs which are achievable in urine.
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165. 165
  Matsuura, M., Nakazawa, H., Hashimoto, T., and Mitsuhashi, S. (1980) Combined Antibacterial Activity of Amoxicillin with Clavulanic Acid against Ampicillin-Resistant Strains. Antimicrob. Agents Chemother. 17, 908– 911, DOI: 10.1128/AAC.17.6.908
  165
  Combined antibacterial activity of amoxicillin with clavulanic acid against ampicillin-resistant strains
  Matsuura, M.; Nakazawa, H.; Hashimoto, T.; Mitsuhashi, S.
  Antimicrobial Agents and Chemotherapy (1980), 17 (6), 908-11CODEN: AMACCQ; ISSN:0066-4804.
  Strains of bacteria resistant to beta-lactam antibiotics have been increasing in no. and are becoming troublesome in clin. medicine. The in vitro antibacterial activity of amoxicillin (I) [26787-78-0] combined with clavulanic acid [58001-44-8] was detd. on selected ampicillin [69-53-4]-resistant clin. isolates. Synergistic effects were produced by I with clavulanic acid against ampicillin-resistant strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and Bacteroides fragilis. Inhibition of the beta-lactamases produced by the ampicillin-resistant strains was confirmed, esp. against the penicillinases mediated by the R factor and the cephalosporinases produced by P. vulgaris and B. fragilis. The inhibitory effect of clavulanic acid against beta-lactamases was irreversible because of the high affinity of clavulanic acid for the enzymes.
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166. 166
  Brogden, R. N., Carmine, A., Heel, R. C., Morley, P. A., Speight, T. M., and Avery, G. S. (1981) Amoxycillin/Clavulanic Acid: A Review of Its Antibacterial Activity, Pharmacokinetics and Therapeutic Use. Drugs 22, 337– 362, DOI: 10.2165/00003495-198122050-00001
  166
  Amoxycillin/clavulanic acid: a review of its antibacterial activity, pharmacokinetics and therapeutic use
  Brogden, R. N.; Carmine, A.; Heel, R. C.; Morley, P. A.; Speight, T. M.; Avery, G. S.
  Drugs (1981), 22 (5), 337-62CODEN: DRUGAY; ISSN:0012-6667.
  A review with many refs. on the pharmacol. of the amoxycillin-clavulanic acid mixt. [79198-29-1].
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167. 167
  Breidenstein, E. B. M., Courvalin, P., and Meziane-Cherif, D. (2015) Antimicrobial Activity of Plectasin NZ2114 in Combination with Cell Wall Targeting Antibiotics Against VanA-Type Enterococcus Faecalis. Microb. Drug Resist. 21, 373– 379, DOI: 10.1089/mdr.2014.0221
  167
  Antimicrobial Activity of Plectasin NZ2114 in Combination with Cell Wall Targeting Antibiotics Against VanA-Type Enterococcus faecalis
  Breidenstein, Elena B. M.; Courvalin, Patrice; Meziane-Cherif, Djalal
  Microbial Drug Resistance (New Rochelle, NY, United States) (2015), 21 (4), 373-379CODEN: MDREFJ; ISSN:1076-6294. (Mary Ann Liebert, Inc.)
  Antimicrobial peptide plectasin targeting bacterial cell wall precursor Lipid II has been reported to be active against benzylpenicillin-resistant Streptococcus pneumoniae but less potent against vancomycin-resistant enterococci than their susceptible counterparts. The aim of this work was to test plectasin NZ2114 in combination with cell wall targeting antibiotics on vancomycin-resistant Enterococcus faecalis. The activity of antibiotic combinations was evaluated against VanA-type vancomycin-resistant E. faecalis strain BM4110/pIP816-1 by disk agar-induction, double-disk assay, detn. of fractional inhibitory concn. (FIC) index, and time-kill curve. The results indicated that plectasin NZ2114 was synergistic in combination with teicoplanin, moenomycin, and dalbavancin but not with vancomycin, telavancin, penicillin G, bacitracin, ramoplanin, daptomycin, and fosfomycin. To gain an insight into the synergism, we tested other cell wall antibiotic combinations. Interestingly, synergy was obsd. between teicoplanin or moenomycin and the majority of the antibiotics tested; however, vancomycin was only synergistic with penicillin G. Other cell wall active antibiotics such as ramoplanin, bacitracin, and fosfomycin did not synergize. It appeared that most of the synergies obsd. involved inhibition of the transglycosylation step in peptidoglycan synthesis. These results suggest that teicoplanin, dalbavancin, vancomycin, and telavancin, although they all bind to the C-terminal D-Ala-D-Ala of Lipid II, might act on different stages of cell wall synthesis.
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168. 168
  Schneider, T. and Sahl, H. G. (2010) An Oldie but a Goodie - Cell Wall Biosynthesis as Antibiotic Target Pathway. Int. J. Med. Microbiol. 300, 161– 169, DOI: 10.1016/j.ijmm.2009.10.005
  168
  An oldie but a goodie - cell wall biosynthesis as antibiotic target pathway
  Schneider, Tanja; Sahl, Hans-Georg
  International Journal of Medical Microbiology (2010), 300 (2-3), 161-169CODEN: IMEMFV; ISSN:1438-4221. (Elsevier GmbH)
  A review. Bacterial cell wall biosynthesis represents the target pathway for penicillin, the first antibiotic that was clin. applied on a large scale. Penicillin, by means of its beta-lactam ring, inhibits a no. of enzymes which participate in inserting monomeric cell wall building blocks into the cell wall polymer and which have been termed penicillin-binding proteins (PBPs). Ever since the introduction of penicillin, hundreds of beta-lactam antibiotics have been developed and details of their mol. activities elaborated. Meanwhile, various addnl. classes of antibiotics have been described, which inhibit the same pathway, yet use target mols. others than the PBPs. Such classes include the glycopeptide antibiotics, lipopeptide and lipodepsipeptide antibiotics, the lantibiotics and various other natural product antibiotics with comparatively complex structures. They usually target the membrane-bound steps of the biosynthesis pathway and the highly conserved lipid-bound intermediates of the building block such as lipid II, which represents a particular "Achilles' heel" for antibiotic attack. With in-depth anal. of the activity of more recently identified inhibitors and with the availability of novel techniques for studying prokaryotic cell biol., new insights were obtained into the mol. organization of the cell wall biosynthesis machinery and its interconnections with other vital cellular processes such as cell division. This, in turn, provides hints for new targets to be exploited and for the development of novel cell wall biosynthesis inhibitors.
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169. 169
  Steinmann, J., Buer, J., Pietschmann, T., and Steinmann, E. (2013) Anti-Infective Properties of Epigallocatechin-3-Gallate (EGCG), a Component of Green Tea. Br. J. Pharmacol. 168, 1059– 1073, DOI: 10.1111/bph.12009
  169
  Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea
  Steinmann, J.; Buer, J.; Pietschmann, T.; Steinmann, E.
  British Journal of Pharmacology (2013), 168 (5), 1059-1073CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
  A review. The consumption of green tea (Camellia sinensis) has been shown to have many physiol. and pharmacol. health benefits. In the past two decades several studies have reported that epigallocatechin-3-gallate (EGCG), the main constituent of green tea, has anti-infective properties. Antiviral activities of EGCG with different modes of action have been demonstrated on diverse families of viruses, such as Retroviridae, Orthomyxoviridae and Flaviviridae and include important human pathogens like human immunodeficiency virus, influenza A virus and the hepatitis C virus. Furthermore, the mol. interferes with the replication cycle of DNA viruses like hepatitis B virus, herpes simplex virus and adenovirus. Most of these studies demonstrated antiviral properties within physiol. concns. of EGCG in vitro. In contrast, the min. inhibitory concns. against bacteria were 10-100-fold higher. Nevertheless, the antibacterial effects of EGCG alone and in combination with different antibiotics have been intensively analyzed against a no. of bacteria including multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Furthermore, the catechin EGCG has antifungal activity against human-pathogenic yeasts like Candida albicans. Although the mechanistic effects of EGCG are not fully understood, there are results indicating that EGCG binds to lipid membranes and affects the folic acid metab. of bacteria and fungi by inhibiting the cytoplasmic enzyme dihydrofolate reductase. This review summarizes the current knowledge and future perspectives on the antibacterial, antifungal and antiviral effects of the green tea constituent EGCG.
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170. 170
  Zhao, W.-H., Hu, Z.-Q., Hara, Y., and Shimamura, T. (2002) Inhibition of Penicillinase by Epigallocatechin Gallate Resulting in Restoration of Antibacterial Activity of Penicillin against Penicillinase-Producing Staphylococcus Aureus. Antimicrob. Agents Chemother. 46, 2266– 2268, DOI: 10.1128/AAC.46.7.2266-2268.2002
  170
  Inhibition of penicillinase by epigallocatechin gallate resulting in restoration of antibacterial activity of penicillin against penicillinase-producing Staphylococcus aureus
  Zhao, Wei-Hua; Hu, Zhi-Qing; Hara, Yukihiko; Shimamura, Tadakatsu
  Antimicrobial Agents and Chemotherapy (2002), 46 (7), 2266-2268CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The combination of epigallocatechin gallate (EGCg, a main constituent of tea catechins) with penicillin showed synergism against 21 clin. isolates of penicillinase-producing Staphylococcus aureus. Besides binding directly to peptidoglycan, the inhibition of penicillinase activity by EGCg is responsible for the synergism. EGCg inhibited the penicillinase activity in a dose-dependent fashion, with a 50% inhibitory concn. of 10 μg/mL.
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171. 171
  Berti, A. D., Theisen, E., Sauer, J.-D., Nonejuie, P., Olson, J., Pogliano, J., Sakoulas, G., Nizet, V., Proctor, R. A., and Rose, W. E. (2016) Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus Aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for Beta-Lactam-Daptomycin Synergy. Antimicrob. Agents Chemother. 60, 451– 458, DOI: 10.1128/AAC.02071-15
  171
  Penicillin binding protein 1 is important in the compensatory response of Staphylococcus aureus to daptomycin-induced membrane damage and is a potential target for β-Lactam-daptomycin synergy
  Berti, Andrew D.; Theisen, Erin; Sauer, John-Demian; Nonejuie, Poochit; Olson, Joshua; Pogliano, Joseph; Sakoulas, George; Nizet, Victor; Proctor, Richard A.; Rose, Warren E.
  Antimicrobial Agents and Chemotherapy (2016), 60 (1), 451-458CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of β-lactam antibiotics. This effect is more pronounced with β-lactam antibiotics that exhibit avid binding to penicillin-binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the pbpA transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of pbpB, pbpC, and pbpD, encoding PBP2, PBP3, and PBP4, resp., remained unchanged. Using a MRSA COL strain with pbpA under an inducible promoter, increased pbpA transcription was accompanied by reduced susceptibility to, and killing by, DAP in vitro. Exposure to β-lactams that preferentially inactivate PBP1 was not assocd. with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-mol. basis. Combination exposure in an in vitro pharmacokinetic/pharmacodynamic model system with β-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAP-nafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO), or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective). Compared to β-lactams with poor PBP1 binding specificity, exposure of S. aureus to DAP plus PBP1-selective β-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP-β-lactam combination therapy for serious MRSA infections, particularly when the β-lactam undermines the PBP1-mediated compensatory response.
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172. 172
  Smith, J. R., Barber, K. E., Raut, A., Aboutaleb, M., Sakoulas, G., and Rybak, M. J. (2015) Beta-Lactam Combinations with Daptomycin Provide Synergy against Vancomycin-Resistant Enterococcus Faecalis and Enterococcus Faecium. J. Antimicrob. Chemother. 70, 1738– 1743, DOI: 10.1093/jac/dkv007
  172
  β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium
  Smith, Jordan R.; Barber, Katie E.; Raut, Animesh; Aboutaleb, Mostafa; Sakoulas, George; Rybak, Michael J.
  Journal of Antimicrobial Chemotherapy (2015), 70 (6), 1738-1743CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. The objective here was to conduct combination MIC and time-kill expts. to evaluate BL synergy with daptomycin against enterococci. Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill expts. Daptomycin at 0.5 × MIC was used in combination with BL at biol. free concn. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labeled daptomycin (BoDipy) expts. Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill expts., ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial redn. at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin expts., ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001). Conclusions: The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clin. research involving daptomycin combinations is warranted.
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173. 173
  Koppen, B. C., Mulder, P. P. G., de Boer, L., Riool, M., Drijfhout, J. W., and Zaat, S. A. J. (2019) Synergistic Microbicidal Effect of Cationic Antimicrobial Peptides and Teicoplanin against Planktonic and Biofilm-Encased Staphylococcus Aureus. Int. J. Antimicrob. Agents 53, 143– 151, DOI: 10.1016/j.ijantimicag.2018.10.002
  173
  Synergistic microbicidal effect of cationic antimicrobial peptides and teicoplanin against planktonic and biofilm-encased Staphylococcus aureus
  Koppen, Bruce C.; Mulder, Patrick P. G.; de Boer, Leonie; Riool, Martijn; Drijfhout, Jan W.; Zaat, Sebastian A. J.
  International Journal of Antimicrobial Agents (2019), 53 (2), 143-151CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
  Antibiotic resistance and biofilm formation are the main reasons for failure in treatment of bacterial infections. This study aimed to identify synergistic combinations of conventional antibiotics and novel synthetic antimicrobial and antibiofilm peptides (SAAPs) inspired by the structures of the natural human cationic peptides LL-37 and thrombocidin-1 (TC-1). The LL-37-inspired lead peptide SAAP-148 was combined with antibiotics of different classes against Staphylococcus aureus, and showed synergy with teicoplanin. Synergy with teicoplanin was also obsd. with LL-37, the LL-37-inspired SAAP-276 and the TC-1-inspired TC84. Interestingly, no synergy was obsd. against Staphylococcus epidermidis. Furthermore, teicoplanin combined with SAAP-148 or SAAP-276 showed strong interaction against S. aureus biofilms. The dltABCD operon and the mprF gene in S. aureus conferred resistance to LL-37, but SAAP-148 proved to be indifferently potent against wild-type, ΔdltA and ΔmprF S. aureus strains. When used alone, relatively high concns. of both LL-37 and teicoplanin (30-120 μM and 4-32 mg/L, resp.) were required to kill S. aureus. Resistance to LL-37 in S. aureus was overcome by combined use of teicoplanin and LL-37. Thus, teicoplanin potentiates peptide LL-37, enhancing the efficacy of the innate defense, and combining the novel peptides with teicoplanin offers potential for enhanced efficacy of treatment of S. aureus infections, including biofilms.
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174. 174
  Fernandez-Cuenca, F., Martinez-Martinez, L., Pascual, A., and Perea, E. J. (2003) In Vitro Activity of Azithromycin in Combination with Amikacin, Ceftazidime, Ciprofloxacin or Imipenem against Clinical Isolates of Acinobacter Baumannii. Chemotherapy 49, 24– 26, DOI: 10.1159/000069774
  174
  In vitro activity of azithromycin in combination with amikacin, ceftazidime, ciprofloxacin or imipenem against clinical isolates of Acinetobacter baumannii
  Fernandez-Cuenca, Felipe; Martinez-Martinez, Luis; Pascual, Alvaro; Perea, Evelio J.
  Chemotherapy (Basel, Switzerland) (2003), 49 (1-2), 24-26CODEN: CHTHBK; ISSN:0009-3157. (S. Karger AG)
  The in vitro activity of the two-drug combinations of azithromycin with amikacin, ceftazidime, ciprofloxacin or imipenem against five clonally unrelated strains of Acinetobacter baumannii were evaluated. Synergy studies were performed by the checkerboard microtiter method. The fractional inhibitory concn. (FIC) index was calcd. for each drug combination. None of the 4 combinations tested was antagonistic. The combination of azithromycin and ceftazidime was synergistic (FIC index ≤0.5) for one strain and partially synergistic (FIC index 0.75) for another strain. An additive effect (FIC index = 1) was obsd. for the combinations of azithromycin with imipenem (two strains) or ceftazidime (one strain). The activities of the other combinations were indifferent (FIC index range from 1.5 to 2.5). It is concluded that azithromycin combined with ceftazidime has moderate synergistic activity against some multiresistant A. baumannii.
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175. 175
  Sertcelik, A., Baran, I., Akinci, E., Mumcuoglu, I., and Bodur, H. (2019) Synergistic Activities of Colistin Combinations with Meropenem, Sulbactam, Minocycline, Disodium Fosfomycin, or Vancomycin Against Different Clones of Carbapenem-Resistant Acinetobacter Baumannii Strains. Microb. Drug Resist. DOI: 10.1089/mdr.2019.0088 .
  There is no corresponding record for this reference.
176. 176
  Langeveld, W. T., Veldhuizen, E. J. A., and Burt, S. A. (2014) Synergy between Essential Oil Components and Antibiotics: A Review. Crit. Rev. Microbiol. 40, 76– 94, DOI: 10.3109/1040841X.2013.763219
  176
  Synergy between essential oil components and antibiotics: a review
  Langeveld, Wendy T.; Veldhuizen, Edwin J. A.; Burt, Sara A.
  Critical Reviews in Microbiology (2014), 40 (1), 76-94CODEN: CRVMAC; ISSN:1040-841X. (Informa Healthcare)
  A review. With the increase in antibiotic-resistant bacteria and the lack of new antibiotics being brought onto the market, alternative strategies need to be found to cope with infections resulting from drug-resistant bacteria. A possible soln. may be to combine existing antibiotics with phytochems. to enhance the efficacy of antibiotics. A group of phytochems. that is said to have such effects, according to in vitro studies, is essential oils (EOs) and their components. Amongst others, EOs contg. carvacrol, cinnamaldehyde, cinnamic acid, eugenol and thymol can have a synergistic effect in combination with antibiotics. Several modes of action have been put forward by which antibiotics and the essential oil components may act synergistically, such as by affecting multiple targets; by physicochem. interactions and inhibiting antibacterial-resistance mechanisms. Many reported assays show additivity or moderate synergism, indicating that EOs may offer possibilities for reducing antibiotic use.
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177. 177
  Owen, L. and Laird, K. (2018) Synchronous Application of Antibiotics and Essential Oils: Dual Mechanisms of Action as a Potential Solution to Antibiotic Resistance. Crit. Rev. Microbiol. 44, 414– 435, DOI: 10.1080/1040841X.2018.1423616
  177
  Synchronous application of antibiotics and essential oils: dual mechanisms of action as a potential solution to antibiotic resistance
  Owen, Lucy; Laird, Katie
  Critical Reviews in Microbiology (2018), 44 (4), 414-435CODEN: CRVMAC; ISSN:1040-841X. (Taylor & Francis Ltd.)
  A review. Antibiotic resistance has increased dramatically in recent years, yet the antibiotic pipeline has stalled. New therapies are therefore needed to continue treating antibiotic resistant infections. One potential strategy currently being explored is the use of non-antibiotic compds. to potentiate the activity of currently employed antibiotics. Many natural products including Essential Oils (EOs) possess broad spectrum antibacterial activity and so have been investigated for this purpose. This article aims to review recent literature concerning the antibacterial activity of EOs and their interactions with antibiotics, with consideration of dual mechanisms of action of EOs and antibiotics as a potential soln. to antibiotic resistance. Synergistic interactions between EOs and their components with antibiotics have been reported, including several instances of antibiotic resensitization in resistant isolates, in support of this strategy to control antibiotic resistance. However, a lack of consistency in methods and interpretation criteria makes drawing conclusions of efficacy of studied combinations difficult. Synergistic effects are often not explored beyond preliminary identification of antibacterial interactions and mechanism of action is rarely defined, despite many hypotheses and recommendations for future study. Much work is needed to fully understand EO-antibiotic assocns. before they can be further developed into novel antibacterial formulations.
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178. 178
  Mathur, H., Field, D., Rea, M. C., Cotter, P. D., Hill, C., and Ross, R. P. (2017) Bacteriocin-Antimicrobial Synergy: A Medical and Food Perspective. Front. Microbiol. 8, 1205, DOI: 10.3389/fmicb.2017.01205
  178
  Bacteriocin-Antimicrobial Synergy: A Medical and Food Perspective
  Mathur Harsh; Rea Mary C; Cotter Paul D; Mathur Harsh; Field Des; Rea Mary C; Cotter Paul D; Hill Colin; Ross R Paul; Field Des; Hill Colin; Ross R Paul
  Frontiers in microbiology (2017), 8 (), 1205 ISSN:1664-302X.
  The continuing emergence of multi-drug resistant pathogens has sparked an interest in seeking alternative therapeutic options. Antimicrobial combinatorial therapy is one such avenue. A number of studies have been conducted, involving combinations of bacteriocins with other antimicrobials, to circumvent the development of antimicrobial resistance and/or increase antimicrobial potency. Such bacteriocin-antimicrobial combinations could have tremendous value, in terms of reducing the likelihood of resistance development due to the involvement of two distinct mechanisms of antimicrobial action. Furthermore, antimicrobial synergistic interactions may also have potential financial implications in terms of decreasing the costs of treatment by reducing the concentration of an expensive antimicrobial and utilizing it in combination with an inexpensive one. In addition, combinatorial therapies with bacteriocins can broaden antimicrobial spectra and/or result in a reduction in the concentration of an antibiotic required for effective treatments to the extent that potentially toxic or adverse side effects can be reduced or eliminated. Here, we review studies in which bacteriocins were found to be effective in combination with other antimicrobials, with a view to targeting clinical and/or food-borne pathogens. Furthermore, we discuss some of the bottlenecks which are currently hindering the development of bacteriocins as viable therapeutic options, as well as addressing the need to exercise caution when attempting to predict clinical outcomes of bacteriocin-antimicrobial combinations.
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179. 179
  Wolska, K. I., Grzes, K., and Kurek, A. (2012) Synergy between Novel Antimicrobials and Conventional Antibiotics or Bacteriocins. Pol. J. Microbiol. 61, 95– 104, DOI: 10.33073/pjm-2012-012
  179
  Synergy between novel antimicrobials and conventional antibiotics or bacteriocins
  Wolska, Krystyna I.; Grzes, Katarzyna; Kurek, Anna
  Polish Journal of Microbiology (2012), 61 (2), 95-104CODEN: PJMOAQ; ISSN:1733-1331. (Polskie Towarzystwo Mikrobiologow)
  A review. Due to the alarming spread of resistance to classic antimicrobial agents, innovative therapeutic methods to combat antibiotic-resistant bacterial pathogens are urgently required. This minireview examines the enhancement of antibiotic efficacy by their combination with new antimicrobials, such as plant-derived compds., metal ions and nanoparticles and bacteriophage lytic enzymes. The mechanisms of the obsd. synergy are also described. The promising results of basic research indicate that in future, combined therapy may be applied in human and veterinary medicine, agriculture and the food industry to combat bacterial pathogens.
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180. 180
  Wittekind, M. and Schuch, R. (2016) Cell Wall Hydrolases and Antibiotics: Exploiting Synergy to Create Efficacious New Antimicrobial Treatments. Curr. Opin. Microbiol. 33, 18– 24, DOI: 10.1016/j.mib.2016.05.006
  180
  Cell wall hydrolases and antibiotics: exploiting synergy to create efficacious new antimicrobial treatments
  Wittekind, Michael; Schuch, Raymond
  Current Opinion in Microbiology (2016), 33 (), 18-24CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)
  A review. Cell wall hydrolases (CWH) are enzymes that build, remodel and degrade peptidoglycan within bacterial cell walls and serve essential roles in cell-wall metab., bacteriophage adsorption and bacteriolysis, environmental niche expansion, as well as eukaryotic innate immune defense against bacterial infection. Some CWHs, when tested as recombinant purified proteins, have been shown to have bactericidal activities both as single agents and in combinations with other antimicrobials, displaying synergies in vitro and potent activities in animal models of infection greater than the single agents alone. We summarize in vitro, in vivo, and mechanistic studies that illustrate ACWH synergy with antibiotics, antimicrobial peptides, and other ACWHs, underscoring the overall synergistic potential of the ACWH class.
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181. 181
  Zusman, O., Avni, T., Leibovici, L., Adler, A., Friberg, L., Stergiopoulou, T., Carmeli, Y., and Paul, M. (2013) Systematic Review and Meta-Analysis of in Vitro Synergy of Polymyxins and Carbapenems. Antimicrob. Agents Chemother. 57, 5104– 5111, DOI: 10.1128/AAC.01230-13
  181
  Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems
  Zusman, Oren; Avni, Tomer; Leibovici, Leonard; Adler, Amos; Friberg, Lena; Stergiopoulou, Theodouli; Carmeli, Yehuda; Paul, Mical
  Antimicrobial Agents and Chemotherapy (2013), 57 (10), 5104-5111CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Our objective was to examine the evidence of in vitro synergy of polymyxin-carbapenem combination therapy against Gram-neg. bacteria (GNB). A systematic review and meta-anal. were performed. All studies examg. in vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concn. index of ≤0.5 or a >2-log redn. in CFU, were pooled sep. for time-kill, checkerboard, and Etest methods in a mixed-effect meta-anal. of rates. We examd. whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for Acinetobacter baumannii, 44% (95% CI, 30 to 59%) for Klebsiella pneumoniae, and 50% (95% CI, 30 to 69%) for Psudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance development in vitro. The combination of a carbapenem with a polymyxin against GNB, esp. A. baumannii, is supported in vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examd. in clin. studies.
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182. 182
  Lenhard, J. R., Nation, R. L., and Tsuji, B. T. (2016) Synergistic Combinations of Polymyxins. Int. J. Antimicrob. Agents 48, 607– 613, DOI: 10.1016/j.ijantimicag.2016.09.014
  182
  Synergistic combinations of polymyxins
  Lenhard, Justin R.; Nation, Roger L.; Tsuji, Brian T.
  International Journal of Antimicrobial Agents (2016), 48 (6), 607-613CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
  A review. The proliferation of extensively drug-resistant Gram-neg. pathogens has necessitated the therapeutic use of colistin and polymyxin B. However, treatment failures with polymyxin monotherapies and the emergence of polymyxin resistance have catalyzed the search for polymyxin combinations that synergistically kill polymyxin-susceptible and -resistant organisms. This mini-review examines recent (2011-2016) in vitro and in vivo studies that have attempted to identify synergistic polymyxin combinations against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Clin. evidence for the use of combination regimens is also discussed.
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183. 183
  Alakomi, H.-L., Saarela, M., and Helander, I. M. (2003) Effect of EDTA on Salmonella Enterica Serovar Typhimurium Involves a Component Not Assignable to Lipopolysaccharide Release. Microbiology 149, 2015– 2021, DOI: 10.1099/mic.0.26312-0
  183
  Effect of EDTA on Salmonella enterica serovar Typhimurium involves a component not assignable to lipopolysaccharide release
  Alakomi, H.-L.; Saarela, M.; Helander, I. M.
  Microbiology (Reading, United Kingdom) (2003), 149 (8), 2015-2021CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
  The effect of EDTA on Salmonella enterica serovar Typhimurium was studied in different growth phases with cells grown with or without Ca2+ and Mg2+ supplementation. EDTA affected the outer membrane much more strongly in the early exponential phase than in the mid- or late exponential phase, as indicated by uptake of 1-N-phenylnaphthylamine (a nonpolar hydrophobic probe, Mr 219) and detergent (SDS) susceptibility. This effect was, however, not paralleled by LPS release (detd. by measuring LPS-specific fatty acids or 14C-labeled LPS in cell-free supernatants, per a standardized cell d.), which remained unchanged as a function of the growth curve. The conclusion from these results is that in the early exponential phase the effect of EDTA in S. enterica involves a component that is independent of LPS release.
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184. 184
  Vaara, M. (1992) Agents That Increase the Permeability of the Outer Membrane. Microbiol. Rev. 56, 395– 411, DOI: 10.1128/MMBR.56.3.395-411.1992
  184
  Agents that increase the permeability of the outer membrane
  Vaara, Martti
  Microbiological Reviews (1992), 56 (3), 395-411CODEN: MBRED3; ISSN:0146-0749.
  A review with 241 refs. on cationic agents and chelators as outer membrane permeabilizers, the mol. mechanism of outer membrane permeability increase, and bacterial strains resistant to the permeabilizers.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXjsFCktQ%253D%253D&md5=2416c67d643c9be119bfb1c0d2323b62
185. 185
  Bellio, P., Luzi, C., Mancini, A., Cracchiolo, S., Passacantando, M., Di Pietro, L., Perilli, M., Amicosante, G., Santucci, S., and Celenza, G. (2018) Cerium Oxide Nanoparticles as Potential Antibiotic Adjuvant. Effects of CeO2 Nanoparticles on Bacterial Outer Membrane Permeability. Biochim. Biophys. Acta, Biomembr. 1860, 2428– 2435, DOI: 10.1016/j.bbamem.2018.07.002
  185
  Cerium oxide nanoparticles as potential antibiotic adjuvant. Effects of CeO2 nanoparticles on bacterial outer membrane permeability
  Bellio, Pierangelo; Luzi, Carla; Mancini, Alisia; Cracchiolo, Salvatore; Passacantando, Maurizio; Di Pietro, Letizia; Perilli, Mariagrazia; Amicosante, Gianfranco; Santucci, Sandro; Celenza, Giuseppe
  Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (11), 2428-2435CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Therapeutic options against Multi Drug Resistant (MDR) pathogens are limited and the overall strategy would be the development of adjuvants able to enhance the activity of therapeutically available antibiotics. Non-specific outer membrane permeabilizer, like metal-oxide nanoparticles, can be used to increase the activity of antibiotics in drug-resistant pathogens. The study aims to investigate the effect of cerium oxide nanoparticles (CeO2 NPs) on bacterial outer membrane permeability and their application in increasing the antibacterial activity of antibiotics against MDR pathogens. The ability of CeO2 NPs to permeabilize Gram-neg. bacterial outer membrane was investigated by calcein-loaded liposomes. The extent of the damage was evaluated using lipid vesicles loaded with FITC-dextran probes. The effect on bacterial outer membrane was evaluated by measuring the coeff. of permeability at increasing concns. of CeO2 NPs. The interaction between CeO2 NPs and beta-lactams was evaluated by chequerboard assay against a Klebsiella pneumoniae clin. isolate expressing high levels of resistance against those antibiotics. Calcein leakage increases as NPs concns. increase while no leakage was obsd. in FITC-dextran loaded liposomes. In Escherichia coli the outer membrane permeability coeff. increases in presence of CeO2 NPs. The antibacterial activity of beta-lactam antibiotics against K. pneumoniae was enhanced when combined with NPs. CeO2 NPs increases the effectiveness of antimicrobials which activity is compromised by drug resistance mechanisms. The synergistic effect is the result of the interaction of NPs with the bacterial outer membrane. The low toxicity of CeO2 NPs makes them attractive as antibiotic adjuvants against MDR pathogens.
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186. 186
  Saikia, K. and Chaudhary, N. (2018) Antimicrobial Peptides from C-Terminal Amphipathic Region of E. Coli FtsA. Biochim. Biophys. Acta, Biomembr. 1860, 2506– 2514, DOI: 10.1016/j.bbamem.2018.09.011
  186
  Antimicrobial peptides from C-terminal amphipathic region of E. coli FtsA
  Saikia, Karabi; Chaudhary, Nitin
  Biochimica et Biophysica Acta, Biomembranes (2018), 1860 (12), 2506-2514CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
  Antimicrobial peptides constitute an indispensable component of innate immune system in organisms ranging from bacteria to man. Despite this, peptides lag far behind the conventional antibiotics in treating infections. The menace of multidrug-resistant bacteria, however, has revived the antimicrobial peptide research. We reasoned that the membrane-binding regions of bacterial proteins could be purposed to combat them. Here, we identify potent antimicrobial peptides from the C-terminal amphipathic helix of E. coli FtsA protein. The 11 and 13-residue peptides exhibited activity against E. coli, gentamicin-resistant MRSA, and C. albicans. The activity is little affected by the presence of salt and divalent cations. The peptides preferentially bind to the neg.-charged membranes as indicated by tryptophan fluorescence studies. The peptides permeabilize the E. coli outer and inner membranes at very promising concns. suggesting membrane-disruption as one of the mechanisms of killing.
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187. 187
  Wiese, A., Gutsmann, T., and Seydel, U. (2003) Towards Antibacterial Strategies: Studies on the Mechanisms of Interaction between Antibacterial Peptides and Model Membranes. J. Endotoxin Res. 9, 67– 84, DOI: 10.1179/096805103125001441
  187
  Towards antibacterial strategies: studies on the mechanisms of interaction between antibacterial peptides and model membranes
  Wiese, Andre; Gutsmann, Thomas; Seydel, Ulrich
  Journal of Endotoxin Research (2003), 9 (2), 67-84CODEN: JENREB; ISSN:0968-0519. (Maney Publishing)
  A review. Lipopolysaccharides (LPSs) play a dual role as inflammation-inducing and as membrane-forming mols. The former role attracts significantly more attention from scientists, possibly because it is more closely related to sepsis and septic shock. This review aims to focus the reader's attention to the other role, the function of LPS as the major constituent of the outer layer of the outer membrane of Gram-neg. bacteria, in particular those of enterobacterial strains. In this function, LPS is a necessary component of the cell envelope and guarantees survival of the bacterial organism. At the same time, it represents the first target for attacking mols. which may either be synthesized by the host's innate or adaptive immune system or administered to the human body. The interaction of these mols. with the outer membrane may not only directly cause the death of the bacterial organism, but may also lead to the release of LPS into the circulation. Here, we review membrane model systems and their application for the study of mol. mechanisms of interaction of peptides such as those of the human complement system, the bactericidal/permeability-increasing protein (BPI), cationic antibacterial peptide 18 kDa (CAP18) as an example of cathelicidins, defensins, and polymyxin B (PMB). Emphasis is on elec. measurements with a reconstitution system of the lipid matrix of the outer membrane which was established in the authors' lab. as a planar asym. bilayer with one leaflet being composed solely of LPS and the other of the natural phospholipid mixt. The main conclusion, which can be drawn from these investigations, is that LPS and in general its neg. charges are the dominant determinants for specific peptide-membrane interactions. However, the detailed mechanisms of interaction, which finally lead to bacterial killing, may involve further steps and differ for different antibacterial peptides.
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188. 188
  Vaara, M. and Porro, M. (1996) Group of Peptides That Act Synergistically with Hydrophobic Antibiotics against Gram-Negative Enteric Bacteria. Antimicrob. Agents Chemother. 40, 1801– 1805, DOI: 10.1128/AAC.40.8.1801
  188
  Group of peptides that act synergistically with hydrophobic antibiotics against gram-negative enteric bacteria
  Vaara, Martti; Porro, Massimo
  Antimicrobial Agents and Chemotherapy (1996), 40 (8), 1801-1805CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  A synthetic peptide, KFFKFFKFF, consisting of cationic lysine residues and hydrophobic phenylalanine residues was found to sensitize gram-neg. bacteria to hydrophobic and amphipathic antibiotics. At a concn. of 3 μg/mL, it decreased the MIC of rifampin for smooth, encapsulated Escherichia coli by a factor of 300. Other susceptible bacterial species included Enterobacter cloacae, Klebsiella pneumoniae, and Salmonella typhimurium, but Pseudomonas aeruginosa was resistant. Similar results were obtained with another synthetic peptide, IKFLKFLKFL. The fractional inhibitory concn. indexes for the synergism of these peptides with rifampin, erythromycin, fusidic acid, and novobiocin were very close to those detd. for the previously characterized potent outer-membrane-disorganizing agents polymyxin B nonapeptide and deacylpolymyxin B. KFFKFFKFF had direct activity against the gram-pos. organism Micrococcus strain ML36, was strongly hemolytic, and was as active on polymyxin-resistant E. coli mutants as on their parent. These three attributes made KFFKFFKFF different from polymyxin derivs. and similar to cationic detergents, such as cetylpyridinium chloride. However, whereas the MIC of cetylpyridinium chloride for E. coli is low (0.5 to 4 μg/mL), that of KFFKFFKFF is much higher (30 to 100 μg/mL). Other groups of synthetic peptides studied included polymyxin-like peptides with an intrachain disulfide bridge. Their synergism with antibiotics was less marked. Still other peptides, including KEKEKEKEKE and KKKKKKFLFL, lacked any synergism with the probe antibiotics.
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189. 189
  Ando, M., Kamei, R., Komagoe, K., Inoue, T., Yamada, K., and Katsu, T. (2012) In Situ Potentiometric Method to Evaluate Bacterial Outer Membrane-Permeabilizing Ability of Drugs: Example Using Antiprotozoal Diamidines. J. Microbiol. Methods 91, 497– 500, DOI: 10.1016/j.mimet.2012.09.033
  189
  In situ potentiometric method to evaluate bacterial outer membrane-permeabilizing ability of drugs: Example using antiprotozoal diamidines
  Ando, Makoto; Kamei, Rie; Komagoe, Keiko; Inoue, Tsuyoshi; Yamada, Keiichi; Katsu, Takashi
  Journal of Microbiological Methods (2012), 91 (3), 497-500CODEN: JMIMDQ; ISSN:0167-7012. (Elsevier B.V.)
  We introduced a new assay system, combining tyrocidine A and a K+-selective electrode, to evaluate the bacterial outer membrane-permeabilizing ability of drugs. Tyrocidine A, in the presence of an outer membrane permeabilizer, increased the permeability to K+ of the cytoplasmic membrane of Escherichia coli, because this antibiotic could markedly increase the permeability of phospholipid layers constituting the cytoplasmic membrane, while it acted weakly on the outer membrane. Hence, the novel function of agents increasing the permeability of the outer membrane could be examd. directly by monitoring the tyrocidine A-induced leakage of K+ from the bacterial cytoplasm using a K+-selective electrode. We found that antiprotozoal diamidines, such as diminazene, pentamidine, and 4',6-diamidino-2-phenylindole (DAPI), can increase the permeability of the bacterial outer membrane and appropriate lipophilicity is important for diamidines to permeabilize the outer membrane.
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190. 190
  Stokes, J. M., MacNair, C. R., Ilyas, B., French, S., Cote, J.-P., Bouwman, C., Farha, M. A., Sieron, A. O., Whitfield, C., Coombes, B. K., and Brown, E. D. (2017) Pentamidine Sensitizes Gram-Negative Pathogens to Antibiotics and Overcomes Acquired Colistin Resistance. Nat. Microbiol. 2, 17028, DOI: 10.1038/nmicrobiol.2017.28
  190
  Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance
  Stokes Jonathan M; MacNair Craig R; Ilyas Bushra; French Shawn; Cote Jean-Philippe; Farha Maya A; Sieron Arthur O; Coombes Brian K; Brown Eric D; Bouwman Catrien; Whitfield Chris
  Nature microbiology (2017), 2 (), 17028 ISSN:.
  The increasing use of polymyxins(1) in addition to the dissemination of plasmid-borne colistin resistance threatens to cause a serious breach in our last line of defence against multidrug-resistant Gram-negative pathogens, and heralds the emergence of truly pan-resistant infections. Colistin resistance often arises through covalent modification of lipid A with cationic residues such as phosphoethanolamine-as is mediated by Mcr-1 (ref. 2)-which reduce the affinity of polymyxins for lipopolysaccharide(3). Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections(4). The difficulty in eradicating Gram-negative bacteria is largely due to their highly impermeable outer membrane, which serves as a barrier to many otherwise effective antibiotics(5). Here, we describe an unconventional screening platform designed to enrich for non-lethal, outer-membrane-active compounds with potential as adjuvants for conventional antibiotics. This approach identified the antiprotozoal drug pentamidine(6) as an effective perturbant of the Gram-negative outer membrane through its interaction with lipopolysaccharide. Pentamidine displayed synergy with antibiotics typically restricted to Gram-positive bacteria, yielding effective drug combinations with activity against a wide range of Gram-negative pathogens in vitro, and against systemic Acinetobacter baumannii infections in mice. Notably, the adjuvant activity of pentamidine persisted in polymyxin-resistant bacteria in vitro and in vivo. Overall, pentamidine and its structural analogues represent unexploited molecules for the treatment of Gram-negative infections, particularly those having acquired polymyxin resistance determinants.
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191. 191
  Yarlagadda, V., Manjunath, G. B., Sarkar, P., Akkapeddi, P., Paramanandham, K., Shome, B. R., Ravikumar, R., and Haldar, J. (2016) Glycopeptide Antibiotic To Overcome the Intrinsic Resistance of Gram-Negative Bacteria. ACS Infect. Dis. 2, 132– 139, DOI: 10.1021/acsinfecdis.5b00114
  191
  Glycopeptide antibiotics to overcome the intrinsic resistance of Gram-negative bacteria
  Yarlagadda, Venkateswarlu; Manjunath, Goutham B.; Sarkar, Paramita; Akkapeddi, Padma; Paramanandham, Krishnamoorthy; Shome, Bibek R.; Ravikumar, Raju; Haldar, Jayanta
  ACS Infectious Diseases (2016), 2 (2), 132-139CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  The emergence of drug resistance along with a declining pipeline of clin. useful antibiotics has made it vital to develop more effective antimicrobial therapeutics, particularly against difficult-to-treat Gram-neg. pathogens (GNPs). Many antibacterial agents, including glycopeptide antibiotics such as vancomycin, are inherently inactive toward GNPs because of their inability to cross the outer membrane of these pathogens. Here, the authors demonstrate that lipophilic cationic (permanent pos. charge) vancomycin analogs were able to permeabilize the outer membrane of GNPs and overcome the inherent resistance of GNPs toward glycopeptides. Unlike vancomycin, these analogs were shown to have a high activity against a variety of multidrug-resistant clin. isolates such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the murine model of carbapenem-resistant A. baumannii infection, the optimized compd. showed potent activity with no obsd. toxicity. The notable activity of these compds. is attributed to the incorporation of new membrane disruption mechanisms (cytoplasmic membrane depolarization along with outer and inner (cytoplasmic) membrane permeabilization) into vancomycin.
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192. 192
  Zhou, L., van Heel, A. J., Montalban-Lopez, M., and Kuipers, O. P. (2016) Potentiating the Activity of Nisin against Escherichia Coli. Front. Cell Dev. Biol. 4, 7, DOI: 10.3389/fcell.2016.00007
  192
  Potentiating the Activity of Nisin against Escherichia coli
  Zhou Liang; van Heel Auke J; Montalban-Lopez Manuel; Kuipers Oscar P
  Frontiers in cell and developmental biology (2016), 4 (), 7 ISSN:2296-634X.
  Lantibiotics are antimicrobial (methyl)lanthionine-containing peptides produced by various Gram-positive bacteria. The model lantibiotic, nisin, binds lipid II in the cell membrane. Additionally, after binding it can insert into the membrane creating a pore. Nisin can efficiently inhibit the growth of Gram-positive bacteria and resistance is rarely observed. However, the activity of lantibiotics is at least 100-fold lower against certain Gram-negative bacteria. This is caused by the fact that Gram-negative bacteria have an outer membrane that hinders the peptides to reach lipid II, which is located in the inner membrane. Improving the activity of lantibiotics against Gram-negative bacteria could be achieved if the outer membrane traversing efficiency is increased. Here, several anti-Gram-negative peptides (e.g., apidaecin 1b, oncocin), or parts thereof, were fused to the C-terminus of either a truncated version of nisin containing the first three/five rings or full length nisin. The activities of these fusion peptides were tested against Gram-negative pathogens. Our results showed that when an eight amino acids (PRPPHPRL) tail from apidaecin 1b was attached to nisin, the activity of nisin against Escherichia coli CECT101 was increased more than two times. This research presents a new and promising method to increase the anti-Gram-negative activity of lantibiotics.
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193. 193
  Li, Q., Montalban-Lopez, M., and Kuipers, O. P. (2018) Increasing the Antimicrobial Activity of Nisin-Based Lantibiotics against Gram-Negative Pathogens. Appl. Environ. Microbiol. 84, e00052-18 DOI: 10.1128/AEM.00052-18
  There is no corresponding record for this reference.
194. 194
  Schweizer, F. (2019) Enhancing Uptake of Antibiotics into Gram-Negative Bacteria Using Nonribosome-Targeting Aminoglycoside-Based Adjuvants. Future Med. Chem. 11, 1519– 1522, DOI: 10.4155/fmc-2019-0131
  194
  Enhancing uptake of antibiotics into Gram-negative bacteria using nonribosome-targeting aminoglycoside-based adjuvants
  Schweizer, Frank
  Future Medicinal Chemistry (2019), 11 (13), 1519-1522CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
  A review. This article discusses about development and discovery of current strategies to enhance uptake of antibiotics into Gram-neg. bacteria such as carbapenem resistant Pseudomonas aeruginosa, carbapenem resistant Acinetobacter baumannii and carbapenem resistant Enterobacteriaceae using nonribosome targeting aminoglycoside based adjuvants which cause threat to human health.
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195. 195
  Raulston, J. E. and Montie, T. C. (1989) Early Cell Envelope Alterations by Tobramycin Associated with Its Lethal Action on Pseudomonas Aeruginosa. Microbiology 135, 3023– 3034, DOI: 10.1099/00221287-135-11-3023
  195
  Early cell envelope alterations by tobramycin associated with its lethal action on Pseudomonas aeruginosa
  Raulston, Jane E.; Montie, Thomas C.
  Journal of General Microbiology (1989), 135 (11), 3023-34CODEN: JGMIAN; ISSN:0022-1287.
  The immediate activities of the aminoglycoside antibiotic tobramycin were investigated in P. aeruginosa PAO1. The lethal action of a low concn. of tobramycin (8 μg/mL) occurred rapidly (1-3 min) and was assocd. with leakage of certain cellular components into the supernatant. The presence of Mg at the time of initial exposure protected cells by preventing uptake of tobramycin; however, Mg addn. following a brief exposure did not restore viability. Analyses of supernatant material revealed a rapid 2-fold increase in protein released following tobramycin treatment. A prominent 29 kDa protein obsd. by SDS-PAGE in the released material was identified as the periplasmic β-lactamase. Brief exposure to tobramycin did not result in major morphol. damage or cell lysis as obsd. by transmission electron microscopy, and release of lipopolysaccharide was not a primary event. Although activity at the ribosomal level was obsd. by 2-3 min, leakage was detected after only 1 min. These data indicate that leakage of cellular components, particularly β-lactamase, occurs simultaneously, if not prior to inhibition of protein synthesis by tobramycin.
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196. 196
  Bulitta, J. B., Ly, N. S., Landersdorfer, C. B., Wanigaratne, N. A., Velkov, T., Yadav, R., Oliver, A., Martin, L., Shin, B. S., Forrest, A., and Tsuji, B. T. (2015) Two Mechanisms of Killing of Pseudomonas Aeruginosa by Tobramycin Assessed at Multiple Inocula via Mechanism-Based Modeling. Antimicrob. Agents Chemother. 59, 2315– 2327, DOI: 10.1128/AAC.04099-14
  196
  Two mechanisms of killing of Pseudomonas aeruginosa by tobramycin assessed at multiple inocula via mechanism-based modeling
  Bulitta, Jurgen B.; Ly, Neang S.; Landersdorfer, Cornelia B.; Wanigaratne, Nicholin A.; Velkov, Tony; Yadav, Rajbharan; Oliver, Antonio; Martin, Lisandra; Shin, Beom Soo; Forrest, Alan; Tsuji, Brian T.
  Antimicrobial Agents and Chemotherapy (2015), 59 (4), 2315-2327CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-neg. bacteria remains poorly characterized. Here, the authors developed a novel quant. model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three Pseudomonas aeruginosa strains. At low-intermediate tobramycin concns. (<4 mg/L), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concns. (≥8 mg/L). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 108.9 CFU/mL inoculum than that at the lower inocula. At 1 to 4 mg/L tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be crit. to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quant. model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.
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197. 197
  Yang, X., Goswami, S., Gorityala, B. K., Domalaon, R., Lyu, Y., Kumar, A., Zhanel, G. G., and Schweizer, F. (2017) A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria. J. Med. Chem. 60, 3913– 3932, DOI: 10.1021/acs.jmedchem.7b00156
  197
  A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria
  Yang, Xuan; Goswami, Sudeep; Gorityala, Bala Kishan; Domalaon, Ronald; Lyu, Yinfeng; Kumar, Ayush; Zhanel, George G.; Schweizer, Frank
  Journal of Medicinal Chemistry (2017), 60 (9), 3913-3932CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Drug efflux mechanisms interact synergistically with the outer membrane permeability barrier of Gram-neg. bacteria leading to intrinsic resistance that presents a major challenge for antibiotic drug development. Efflux pump inhibitors (EPIs) which block the efflux of antibiotics synergize antibiotics but the clin. development of EPI/antibiotic combination therapy to treat multidrug-resistant (MDR) Gram-neg. infections has been challenging. This is in part caused by the inefficiency of current EPIs to penetrate the outer membrane and resist efflux. The authors demonstrate that conjugation of a tobramycin (TOB) vector to EPIs like NMP, paroxetine or DBP enhances synergy and efficacy of EPIs in combination with tetracycline antibiotics against MDR Gram-neg. bacteria including Pseudomonas aeruginosa. Besides potentiating tetracycline antibiotics TOB-EPI conjugates can also suppress resistance development to the tetracycline antibiotic minocycline thereby providing a strategy to develop more effective adjuvants to rescue tetracycline antibiotics from resistance in MDR Gram-neg. bacteria.
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198. 198
  Gorityala, B. K., Guchhait, G., Goswami, S., Fernando, D. M., Kumar, A., Zhanel, G. G., and Schweizer, F. (2016) Hybrid Antibiotic Overcomes Resistance in P. Aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux. J. Med. Chem. 59, 8441– 8455, DOI: 10.1021/acs.jmedchem.6b00867
  198
  Hybrid Antibiotic Overcomes Resistance in P. aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux
  Gorityala, Bala Kishan; Guchhait, Goutam; Goswami, Sudeep; Fernando, Dinesh M.; Kumar, Ayush; Zhanel, George G.; Schweizer, Frank
  Journal of Medicinal Chemistry (2016), 59 (18), 8441-8455CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. The authors have discovered a tobramycin-moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concn. (MIC) for the hybrid while moxifloxacin or tobramycin resulted in a 16x- and 512x-fold increase in MIC. Although the hybrid possesses potent activity against MDR P. aeruginosa isolates the activity can be synergized when used in combination with other classes of antibiotics.
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199. 199
  Gorityala, B. K., Guchhait, G., Fernando, D. M., Deo, S., McKenna, S. A., Zhanel, G. G., Kumar, A., and Schweizer, F. (2016) Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas Aeruginosa and Enhance Fluoroquinolone Efficacy. Angew. Chem., Int. Ed. 55, 555– 559, DOI: 10.1002/anie.201508330
  199
  Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy
  Gorityala, Bala Kishan; Guchhait, Goutam; Fernando, Dinesh M.; Deo, Soumya; McKenna, Sean A.; Zhanel, George G.; Kumar, Ayush; Schweizer, Frank
  Angewandte Chemie, International Edition (2016), 55 (2), 555-559CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β-lactam antibiotics and β-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-neg. pathogens has been challenging. The authors describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are sepd. by a C12 tether, is crit. for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.
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200. 200
  Idowu, T., Ammeter, D., Arthur, G., Zhanel, G. G., and Schweizer, F. (2019) Potentiation of Beta-Lactam Antibiotics and Beta-Lactam/Beta-Lactamase Inhibitor Combinations against MDR and XDR Pseudomonas Aeruginosa Using Non-Ribosomal Tobramycin-Cyclam Conjugates. J. Antimicrob. Chemother. 74, 2640– 2648, DOI: 10.1093/jac/dkz228
  200
  Potentiation of beta-lactam antibiotics and beta-lactam/beta-lactamase inhibitor combinations against MDR and XDR Pseudomonas aeruginosa using non-ribosomal tobramycin-cyclam conjugates
  Idowu, Temilolu; Ammeter, Derek; Arthur, Gilbert; Zhanel, George G.; Schweizer, Frank
  Journal of Antimicrobial Chemotherapy (2019), 74 (9), 2640-2648CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
  Objectives: To develop a multifunctional adjuvantmol. that can rescue β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clin. isolates. Methods: Prepn. of adjuvant was guided by structure-activity relationships, following std. protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold diln. assays. Toxicity was evaluated against porcine erythrocytes, human embryonic kidney (HEK293) cells and liver carcinoma (HepG2) cells via MTS assay. Preliminary in vivo efficacy was evaluated using a Galleria mellonella infection model. Results: Conjugation of tobramycin and cyclam abrogates the ribosomal effects of tobramycin but confers a potent adjuvant property that restores full antibiotic activity of meropenem and aztreonam against carbapenem-resistant P. aeruginosa. Therapeutic levels of susceptibility, as detd. by CLSI susceptibility breakpoints, were attained in several MDR clin. isolates, and time-kill assays revealed a synergistic dose-dependent pharmacodynamic relationship. A triple combination of the adjuvant with ceftazidime/avibactam (approved), aztreonam/avibactam(Phase III) and meropenem/avibactam enhances the efficacies of β-lactam/β-lactamase inhibitors against recalcitrant strains, suggesting rapid access of the combination to their periplasmic targets. The newly developed adjuvants, and their combinations, were non-haemolytic and non-cytotoxic, and preliminary in vivo evaluation in G. mellonella suggests therapeutic potential for the double and triple combinations. Conclusions: Non-ribosomal tobramycin-cyclam conjugate mitigates the effect of OprD/OprF porin loss in P. aeruginosa and potentiates β-lactam/β-lactamase inhibitors against carbapenem-resistant clin. isolates, highlighting the complexity of resistance to β-lactam antibiotics. Our strategy presents an avenue to further preserve the therapeutic utility of β-lactamantibiotics.
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201. 201
  Idowu, T., Zhanel, G. G., and Schweizer, F. (2020) A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas Aeruginosa and Delays Resistance Development. Antimicrob. Agents Chemother. 64, e02055-19 DOI: 10.1128/AAC.02055-19
  There is no corresponding record for this reference.
202. 202
  Saikia, K. and Chaudhary, N. (2018) Interaction of MreB-Derived Antimicrobial Peptides with Membranes. Biochem. Biophys. Res. Commun. 498, 58– 63, DOI: 10.1016/j.bbrc.2018.02.176
  202
  Interaction of MreB-derived antimicrobial peptides with membranes
  Saikia, Karabi; Chaudhary, Nitin
  Biochemical and Biophysical Research Communications (2018), 498 (1), 58-63CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
  Antimicrobial peptides are crit. components of defense systems in living forms. The activity is conferred largely by the selective membrane-permeabilizing ability. In our earlier work, we derived potent antimicrobial peptides from the 9-residue long, N-terminal amphipathic helix of E. coli MreB protein. The peptides display broad-spectrum activity, killing not only Gram-pos. and Gram-neg. bacteria but opportunistic fungus, Candida albicans as well. These results proved that membrane-binding stretches of bacterial proteins could turn out to be self-harming when applied from outside. Here, we studied the membrane-binding and membrane-perturbing potential of these peptides. Steady-state tryptophan fluorescence studies with tryptophan extended peptides, WMreB1-9 and its N-terminal acetylated analog, Ac-WMreB1-9 show preferential binding to neg.-charged liposomes. Both the peptides cause permeabilization of E. coli inner and outer-membranes. Tryptophan-lacking peptides, though permeabilize the outer-membrane efficiently, little permeabilization of the inner-membrane is obsd. These data attest membrane-destabilization as the mechanism of rapid bacterial killing. This study is expected to motivate the research in identifying microbes' self-sequences to combat them.
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203. 203
  Saikia, K., Sravani, Y. D., Ramakrishnan, V., and Chaudhary, N. (2017) Highly Potent Antimicrobial Peptides from N-Terminal Membrane-Binding Region of E. Coli MreB. Sci. Rep. 7, 42994, DOI: 10.1038/srep42994
  203
  Highly potent antimicrobial peptides from N-terminal membrane-binding region of E. coli MreB
  Saikia, Karabi; Sravani, Yalavarthi Durga; Ramakrishnan, Vibin; Chaudhary, Nitin
  Scientific Reports (2017), 7 (), 42994CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
  We selected the 9-residue-long membrane-binding region of Escherichia coli MreB protein. The 9-residue peptide (C-terminal amide) and its N-terminal acetylated analog displayed broad-spectrum activity, killing Gram-neg. bacteria, Gram-pos. bacteria, and fungi. Extension with a tryptophan residue at the N-terminus drastically improved the activity of the peptides with lethal concns. ≤10 μM against all the organisms tested. The tryptophan-extended peptides caused complete killing of C. albicans as well as gentamicin and methicillin resistant S. aureus at 5 μM concn. Lipid-binding studies and electron microscopic analyses of the peptide-treated microbes suggest membrane disruption as the mechanism of killing.
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204. 204
  Falagas, M. E. and Kasiakou, S. K. (2006) Toxicity of Polymyxins: A Systematic Review of the Evidence from Old and Recent Studies. Crit. Care 10, R27– R27, DOI: 10.1186/cc3995
  There is no corresponding record for this reference.
205. 205
  Vattimo, M. de F. F., Watanabe, M., da Fonseca, C. D., Neiva, L. B. de M., Pessoa, E. A., and Borges, F. T. (2016) Polymyxin B Nephrotoxicity: From Organ to Cell Damage. PLoS One 11, e0161057 DOI: 10.1371/journal.pone.0161057
  205
  Polymyxin B nephrotoxicity: from organ to cell damage
  Vattimo, Maria de Fatima Fernandes; Watanabe, Mirian; Dezoti da Fonseca, Cassiane; Neiva, Luciana Barros de Moura; Pessoa, Edson Andrade; Borges, Fernanda Teixeira
  PLoS One (2016), 11 (8), e0161057/1-e0161057/17CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  Polymyxins have a long history of dose-limiting toxicity, but the underlying mechanism of polymyxin B-induced nephrotoxicity is unclear. This study investigated the link between the nephrotoxic effects of polymyxin B on renal metabolic functions and mitochondrial morphol. in rats and on the structural integrity of LLC-PK1 cells. Fifteen Wistar rats were divided into two groups: Saline group, rats received 3 mL/kg of 0.9% NaCl i.p. (i.p.) once a day for 5 days; Polymyxin B group, rats received 4 mg/kg/day of polymyxin B i.p. once a day for 5 days. Renal function, renal hemodynamics, oxidative stress, mitochondrial injury and histol. characteristics were assessed. Cell membrane damage was evaluated via lactate dehydrogenase and nitric oxide levels, cell viability, and apoptosis in cells exposed to 12.5 μM, 75 μM and 375 μM polymyxin B. Polymyxin B was immunolocated using Lissamine rhodamine-polymyxin B in LLC-PK1 cells. Polymyxin B administration in rats reduced creatinine clearance and increased renal vascular resistance and oxidative damage. Mitochondrial damage was confirmed by electron microscopy and cytosolic localization of cytochrome c. Histol. anal. revealed tubular dilatation and necrosis in the renal cortex. The redn. in cell viability and the increase in apoptosis, lactate dehydrogenase levels and nitric oxide levels confirmed the cytotoxicity of polymyxin B. The incubation of LLC-PK1 cells resulted in mitochondrial localization of polymyxin B. This study demonstrates that polymyxin B nephrotoxicity is characterized by mitochondrial dysfunction and free radical generation in both LLC-PK1 cells and rat kidneys. These data also provide support for clin. studies on the side effects of polymyxin B.
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206. 206
  Pirri, G., Giuliani, A., Nicoletto, S. F., Pizzuto, L., and Rinaldi, A. C. (2009) Lipopeptides as Anti-Infectives: A Practical Perspective. Cent. Eur. J. Biol. 4, 258– 273, DOI: 10.2478/s11535-009-0031-3
  206
  Lipopeptides as anti-infectives: a practical perspective
  Pirri, Giovanna; Giuliani, Andrea; Nicoletto, Silvia Fabiole; Pizzuto, Lorena; Rinaldi, Andrea C.
  Central European Journal of Biology (2009), 4 (3), 258-273CODEN: CEJBAW; ISSN:1895-104X. (Springer GmbH)
  A review. Lipopeptide antibiotics represent an old class of antibiotics that were discovered over 50 years ago, which includes the old polymyxins but also new entries, such as the recently approved daptomycin. They generally consist of a hydrophilic cyclic peptide portion attached to a fatty acid chain which facilitates insertion into the lipid bilayer of bacterial membranes. This review presents an overview of this class of antibiotics, focusing on their therapeutic applications and putting particular emphasis on chem. modifications introduced to improve their activity.
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207. 207
  Vaara, M. and Vaara, T. (1983) Polycations Sensitize Enteric Bacteria to Antibiotics. Antimicrob. Agents Chemother. 24, 107– 113, DOI: 10.1128/AAC.24.1.107
  207
  Polycations sensitize enteric bacteria to antibiotics
  Vaara, Martti; Vaara, Timo
  Antimicrobial Agents and Chemotherapy (1983), 24 (1), 107-13CODEN: AMACCQ; ISSN:0066-4804.
  Polymyxin B nonapeptide, a polymyxin B deriv. which lacks the fatty acyl part and the bactericidal activity of polymyxin, sensitized smooth encapsulated Escherichia coli (O18:K1) and smooth Salmonella typhimurium to hydrophobic antibiotics (novobiocin, fusidic acid, erythromycin, clindamycin, nafcillin, and cloxacillin). The polymyxin B nonapeptide-treated bacteria were as sensitive to these antibiotics as were deep rough mutants. A lysine polymer with 20 lysine residues (lysine20) had a largely similar effect. Larger lysine polymers and the protamine salmine were bactericidal but, at sublethal concns., sensitized the strains to the above antibiotics, whereas lysine4, streptomycin, cytochrome c, lysozyme, and the polyamines cadaverine, spermidine, and spermine had neither bactericidal nor sensitizing activity.
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208. 208
  Vaara, M. and Vaara, T. (1983) Sensitization of Gram-Negative Bacteria to Antibiotics and Complement by a Nontoxic Oligopeptide. Nature 303, 526– 528, DOI: 10.1038/303526a0
  208
  Sensitization of Gram-negative bacteria to antibiotics and complement by a nontoxic oligopeptide
  Vaara, Martti; Vaara, Timo
  Nature (London, United Kingdom) (1983), 303 (5917), 526-8CODEN: NATUAS; ISSN:0028-0836.
  The polymyxin mol. was modified to obtain a compd. that would act to disorganize the bacterial outer membrane and thus make the membrane more permeable to antibiotics and more vulnerable to attack by the complement cascade. Polymyxin B nonapeptide (PMBN), produced from polymyxin B by the action of ficin, at concns. of ≥0.3 μg/mL caused sensitization of Escherichia coli to hydrophobic antibiotics. In addn., similar concns. of PMBN sensitized the E. coli strain to the bactericidal action of both 30 and 10% guinea pig serum. When the serum was absorbed in the cold to remove the possible natural antibodies against the surface structures of the E. coli strain, it lost most of its PMBN-dependent bactericidal activity. Apparently complement, PMBN, and antibodies are all essential components in the bactericidal system, although normal serum suffices as the antibody source.
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209. 209
  Keirstead, N. D., Wagoner, M. P., Bentley, P., Blais, M., Brown, C., Cheatham, L., Ciaccio, P., Dragan, Y., Ferguson, D., Fikes, J. (2014) Early Prediction of Polymyxin-Induced Nephrotoxicity with next-Generation Urinary Kidney Injury Biomarkers. Toxicol. Sci. 137, 278– 291, DOI: 10.1093/toxsci/kft247
  209
  Early Prediction of Polymyxin-Induced Nephrotoxicity With Next-Generation Urinary Kidney Injury Biomarkers
  Keirstead, Natalie D.; Wagoner, Matthew P.; Bentley, Patricia; Blais, Marie; Brown, Crystal; Cheatham, Letitia; Ciaccio, Paul; Dragan, Yvonne; Ferguson, Douglas; Fikes, Jim; Galvin, Melanie; Gupta, Anshul; Hale, Michael; Johnson, Nakpangi; Luo, Wenli; McGrath, Frank; Pietras, Mark; Price, Sally; Sathe, Abhishek G.; Sasaki, Jennifer C.; Snow, Debra; Walsky, Robert L.; Kern, Gunther
  Toxicological Sciences (2014), 137 (2), 278-291CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
  Despite six decades of clin. experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of std. of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) deriv. with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathol. and biomarker anal. of PMBN, an important test of the hypothesis that fatty acid modifications and charge redns. in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathol. injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clin. stds. of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathol. evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.
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210. 210
  Danner, R. L., Joiner, K. A., Rubin, M., Patterson, W. H., Johnson, N., Ayers, K. M., and Parrillo, J. E. (1989) Purification, Toxicity, and Antiendotoxin Activity of Polymyxin B Nonapeptide. Antimicrob. Agents Chemother. 33, 1428– 1434, DOI: 10.1128/AAC.33.9.1428
  210
  Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide
  Danner, Robert L.; Joiner, Keith A.; Rubin, Marc; Patterson, William H.; Johnson, Nelson; Ayers, Kenneth M.; Parrillo, Joseph E.
  Antimicrobial Agents and Chemotherapy (1989), 33 (9), 1428-34CODEN: AMACCQ; ISSN:0066-4804.
  In expts. with lab. animals, polymyxin B nonapeptide (1:5 or 3 mg/kg) did not exhibit the neuromuscular blocking, neurotoxic, or nephrotoxic effects that were obsd. with polymyxin B sulfate. Both polymyxin B and polymyxin B nonapeptide inhibited lipopolysaccharide-induced neutrophil priming in a concn.-dependent manner, but the parent compd., polymyxin B, was 63 times more effective on a wt. basis. The inhibitory activity of both compds., however, diminished rapidly when they were added after the start of the lipopolysaccharide-neutrophil incubation. Thus, polymyxin B nonapeptide is less toxic than polymyxin B and, at the doses tested, lacks the neurotoxicity and nephrotoxicity of the parent compd. Polymyxin B nonapeptide retains the antiendotoxin activity of polymyxin B but is much less potent. These compds. block an early step in the neutrophil priming process, possibly lipopolysaccharide attachment to or insertion into the neutrophil membrane.
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211. 211
  Vaara, M. (2019) Polymyxin Derivatives That Sensitize Gram-Negative Bacteria to Other Antibiotics. Molecules 24, 249, DOI: 10.3390/molecules24020249
  211
  Polymyxin derivatives that sensitize gram-negative bacteria to other antibiotics
  Vaara, Martti
  Molecules (2019), 24 (2), 249/1-249/15CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-neg. bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clin. use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-neg. bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivs. that are less toxic and/or more effective at tolerable doses are currently under preclin. development and their properties have recently been described in several extensive reviews. Other derivs. lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized "permeabilizer" derivs., i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compd. that recently successfully passed the clin. phase 1. Also, a few other permeabilizer compds. are brought up.
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212. 212
  Recacha, E., Machuca, J., Diaz de Alba, P., Ramos-Guelfo, M., Docobo-Perez, F., Rodriguez-Beltran, J., Blazquez, J., Pascual, A., and Rodriguez-Martinez, J. M. (2017) Quinolone Resistance Reversion by Targeting the SOS Response. mBio 8, e00971-17, DOI: 10.1128/mBio.00971-17
  There is no corresponding record for this reference.
213. 213
  Ojha, D. and Patil, K. N. (2019) P-Coumaric Acid Inhibits the Listeria Monocytogenes RecA Protein Functions and SOS Response: An Antimicrobial Target. Biochem. Biophys. Res. Commun. 517, 655– 661, DOI: 10.1016/j.bbrc.2019.07.093
  213
  p-Coumaric acid inhibits the Listeria monocytogenes RecA protein functions and SOS response: An antimicrobial target
  Ojha, Debika; Patil, K. Neelakanteshwar
  Biochemical and Biophysical Research Communications (2019), 517 (4), 655-661CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
  Bacterial RecA plays an important role in the evaluation of antibiotic resistance via stress-induced DNA repair mechanism; SOS response. Accordingly, RecA became an important therapeutic target against antimicrobial resistance. Small mol. inhibitors of RecA may prevent adaptation of antibiotic resistance mutations and the emergence of antimicrobial resistance. In our study, we obsd. that phenolic compd. p-Coumaric acid as potent RecA inhibitor. It inhibited RecA driven biochem. activities in vitro such as ssDNA binding, strand exchange, ATP hydrolysis and RecA coprotease activity of E. coli and L. monocytogenes RecA proteins. The mechanism underlying such inhibitory action of p-Coumaric acid involves its ability to interfere with the DNA binding domain of RecA protein. p-Coumaric acid also potentiates the activity of ciprofloxacin by inhibiting drastic cell survival of L. monocytogenes as well as filamentation process; the bacteria defensive mechanism in response to DNA damage. Addnl., it also blocked the ciprofloxacin induced RecA expression leading to suppression of SOS response in L. monocytogenes. These findings revealed that p-Coumaric acid is a potent RecA inhibitor, and can be used as an adjuvant to the existing antibiotics which not only enhance the shelf-life but also slow down the emergence of antibiotic resistance in bacteria.
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214. 214
  Crane, J. K., Cheema, M. B., Olyer, M. A., and Sutton, M. D. (2018) Zinc Blockade of SOS Response Inhibits Horizontal Transfer of Antibiotic Resistance Genes in Enteric Bacteria. Front. Cell. Infect. Microbiol. 8, 410, DOI: 10.3389/fcimb.2018.00410
  214
  Zinc blockade of SOS response inhibits horizontal transfer of antibiotic resistance genes in enteric bacteria
  Crane, John K.; Cheema, Muhammad B.; Olyer, Michael A.; Sutton, Mark D.
  Frontiers in Cellular and Infection Microbiology (2018), 8 (), 410CODEN: FCIMAB; ISSN:2235-2988. (Frontiers Media S.A.)
  The SOS response is a conserved response to DNA damage that is found in Gram-neg. and Gram-pos. bacteria. When DNA damage is sustained and severe, activation of error-prone DNA polymerases can induce a higher mutation rate than is normally obsd., which is called the SOS mutator phenotype or hypermutation. We previously showed that zinc blocked the hypermutation response induced by quinolone antibiotics and mitomycin C in Escherichia coli and Klebsiella pneumoniae. In this study, we demonstrate that zinc blocks the SOS-induced development of chloramphenicol resistance in Enterobacter cloacae. Zinc also blocked the transfer of an extended spectrum beta-lactamase (ESBL) gene from Enterobacter to a susceptible E. coli strain. A zinc ionophore, zinc pyrithione, was ∼100-fold more potent than zinc salts in inhibition of ciprofloxacin-induced hypermutation in E. cloacae. Other divalent metals, such as iron and manganese, failed to inhibit these responses. Electrophoretic mobility shift assays (EMSAs) revealed that zinc, but not iron or manganese, blocked the ability of the E. coli RecA protein to bind to single-stranded DNA, an important early step in the recognition of DNA damage in enteric bacteria. This suggests a mechanism for zinc's inhibitory effects on bacterial SOS responses, including hypermutation.
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215. 215
  Xue, J., Moyer, A., Peng, B., Wu, J., Hannafon, B. N., and Ding, W.-Q. (2014) Chloroquine Is a Zinc Ionophore. PLoS One 9, e109180 DOI: 10.1371/journal.pone.0109180
  215
  Chloroquine is a zinc ionophore
  Xue, Jing; Moyer, Amanda; Peng, Bing; Wu, Jinchang; Hannafon, Bethany N.; Ding, Wei-Qun
  PLoS One (2014), 9 (10), e109180/1-e109180/6, 6 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  Chloroquine is an established antimalarial agent that has been recently tested in clin. trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780). Chloroquine enhanced zinc uptake by A2780 cells in a concn.-dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compd., indicating the specificity of the zinc uptake. Furthermore, addn. of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examn. of intracellular zinc distribution demonstrated that free zinc ions are more concd. in the lysosomes after addn. of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine's cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine's anticancer activity.
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216. 216
  Mo, C. Y., Culyba, M. J., Selwood, T., Kubiak, J. M., Hostetler, Z. M., Jurewicz, A. J., Keller, P. M., Pope, A. J., Quinn, A., Schneck, J., Widdowson, K. L., and Kohli, R. M. (2018) Inhibitors of LexA Autoproteolysis and the Bacterial SOS Response Discovered by an Academic-Industry Partnership. ACS Infect. Dis. 4, 349– 359, DOI: 10.1021/acsinfecdis.7b00122
  216
  Inhibitors of LexA Autoproteolysis and the Bacterial SOS Response Discovered by an Academic-Industry Partnership
  Mo, Charlie Y.; Culyba, Matthew J.; Selwood, Trevor; Kubiak, Jeffrey M.; Hostetler, Zachary M.; Jurewicz, Anthony J.; Keller, Paul M.; Pope, Andrew J.; Quinn, Amy; Schneck, Jessica; Widdowson, Katherine L.; Kohli, Rahul M.
  ACS Infectious Diseases (2018), 4 (3), 349-359CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  The RecA/LexA axis of the bacterial DNA damage (SOS) response is a promising, yet nontraditional, drug target. The SOS response is initiated upon genotoxic stress, when RecA, a DNA damage sensor, induces LexA, the SOS repressor, to undergo autoproteolysis, thereby derepressing downstream genes that can mediate DNA repair and accelerate mutagenesis. As genetic inhibition of the SOS response sensitizes bacteria to DNA damaging antibiotics and decreases acquired resistance, inhibitors of the RecA/LexA axis could potentiate our current antibiotic arsenal. Compds. targeting RecA, which has many mammalian homologues, have been reported; however, small-mols. targeting LexA autoproteolysis, a reaction unique to the prokaryotic SOS response, have remained elusive. Here, we describe the logistics and accomplishments of an academic-industry partnership formed to pursue inhibitors against the RecA/LexA axis. A novel fluorescence polarization assay reporting on RecA-induced self-cleavage of LexA enabled the screening of 1.8 million compds. Follow-up studies on select leads show distinct activity patterns in orthogonal assays, including several with activity in cell-based assays reporting on SOS activation. Mechanistic assays demonstrate that we have identified first-in-class small mols. that specifically target the LexA autoproteolysis step in SOS activation. Our efforts establish a realistic example for navigating academic-industry partnerships in pursuit of anti-infective drugs and offer starting points for dedicated lead optimization of SOS inhibitors that could act as adjuvants for current antibiotics.
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217. 217
  Lim, C. S. Q., Ha, K. P., Clarke, R. S., Gavin, L.-A., Cook, D. T., Hutton, J. A., Sutherell, C. L., Edwards, A. M., Evans, L. E., Tate, E. W., and Lanyon-Hogg, T. (2019) Identification of a Potent Small-Molecule Inhibitor of Bacterial DNA Repair That Potentiates Quinolone Antibiotic Activity in Methicillin-Resistant Staphylococcus Aureus. Bioorg. Med. Chem. 27, 114962, DOI: 10.1016/j.bmc.2019.06.025
  217
  Identification of a potent small-molecule inhibitor of bacterial DNA repair that potentiates quinolone antibiotic activity in methicillin-resistant Staphylococcus aureus
  Lim, Carine S. Q.; Ha, Kam Pou; Clarke, Rebecca S.; Gavin, Leigh-Anne; Cook, Declan T.; Hutton, Jennie A.; Sutherell, Charlotte L.; Edwards, Andrew M.; Evans, Lindsay E.; Tate, Edward W.; Lanyon-Hogg, Thomas
  Bioorganic & Medicinal Chemistry (2019), 27 (20), 114962CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  The global emergence of antibiotic resistance is 1 of the most serious challenges facing modern medicine. There is an urgent need for validation of new drug targets and the development of small mols. with novel mechanisms of action. We therefore sought to inhibit bacterial DNA repair mediated by the AddAB/RecBCD protein complexes as a means to sensitize bacteria to DNA damage caused by the host immune system or quinolone antibiotics. A rational, hypothesis-driven compd. optimization identified I as a cell-active, nanomolar potency compd. I sensitized multidrug-resistant Staphylococcus aureus to the fluoroquinolone antibiotic ciprofloxacin, where resistance results from a point mutation in the fluoroquinolone target, DNA gyrase. Cellular reporter assays indicated I inhibited the bacterial SOS-response to DNA damage, and compd.-functionalized Sepharose successfully pulled-down the AddAB repair complex. This work provides validation of bacterial DNA repair as a novel therapeutic target and delivers I as a tool mol. and starting point for therapeutic development to address the pressing challenge of antibiotic resistance.
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218. 218
  Lee, S., Hinz, A., Bauerle, E., Angermeyer, A., Juhaszova, K., Kaneko, Y., Singh, P. K., and Manoil, C. (2009) Targeting a Bacterial Stress Response to Enhance Antibiotic Action. Proc. Natl. Acad. Sci. U. S. A. 106, 14570– 14575, DOI: 10.1073/pnas.0903619106
  218
  Targeting a bacterial stress response to enhance antibiotic action
  Lee, Samuel; Hinz, Aaron; Bauerle, Elizabeth; Angermeyer, Angus; Juhaszova, Katy; Kaneko, Yukihiro; Singh, Pradeep K.; Manoil, Colin
  Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (34), 14570-14575, S14570/1-S14570/16CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  This report describes the identification and anal. of a 2-component regulator of Pseudomonas aeruginosa that is a potential aminoglycoside antibiotic combination therapy target. The regulator, AmgRS, was identified in a screen of a comprehensive, defined transposon mutant library for functions whose inactivation increased tobramycin sensitivity. AmgRS mutations enhanced aminoglycoside action against bacteria grown planktonically and in antibiotic tolerant biofilms, against genetically resistant clin. isolates, and in lethal infections of mice. Drugs targeting AmgRS would thus be expected to enhance the clin. efficacy of aminoglycosides. Unexpectedly, the loss of AmgRS reduced virulence in the absence of antibiotics, indicating that its inactivation could protect against infection directly as well as by enhancing aminoglycoside action. Transcription profiling and phenotypic anal. suggested that AmgRS controls an adaptive response to membrane stress, which can be caused by aminoglycoside-induced translational misreading. These results help validate AmgRS as a potential antibiotic combination target for P. aeruginosa and indicate that fundamental stress responses may be a valuable general source of such targets.
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219. 219
  Poole, K., Gilmour, C., Farha, M. A., Mullen, E., Lau, C. H.-F., and Brown, E. D. (2016) Potentiation of Aminoglycoside Activity in Pseudomonas Aeruginosa by Targeting the AmgRS Envelope Stress-Responsive Two-Component System. Antimicrob. Agents Chemother. 60, 3509– 3518, DOI: 10.1128/AAC.03069-15
  219
  Potentiation of aminoglycoside activity in Pseudomonas aeruginosa by targeting the AmgRS envelope stress-responsive two-component system
  Poole, Keith; Gilmour, Christie; Farha, Maya A.; Mullen, Erin; Lau, Calvin Ho-Fung; Brown, Eric D.
  Antimicrobial Agents and Chemotherapy (2016), 60 (6), 3509-3518CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  A screen for agents that potentiated the activity of paromomycin (PAR), a 4,5-linked aminoglycoside (AG), against wild-type Pseudomonas aeruginosa identified the RNA polymerase inhibitor rifampin (RIF). RIF potentiated addnl. 4,5-linked AGs, such as neomycin and ribostamycin, but not the clin. important 4,6-linked AGs amikacin and gentamicin. Potentiation was absent in a mutant lacking the AmgRS envelope stress response two-component system (TCS), which protects the organism from AG-generated membrane-damaging aberrant polypeptides and, thus, promotes AG resistance, an indication that RIF was acting via this TCS in potentiating 4,5-linked AG activity. Potentiation was also absent in a RIF-resistant RNA polymerase mutant, consistent with its potentiation of AG activity being dependent on RNA polymerase perturbation. PAR-inducible expression of the AmgRS-dependent genes htpX and yccA was reduced by RIF, suggesting that AG activation of this TCS was compromised by this agent. Still, RIF did not compromise the membrane-protective activity of AmgRS, an indication that it impacted some other function of this TCS. RIF potentiated the activities of 4,5-linked AGs against several AG-resistant clin. isolates, in two cases also potentiating the activity of the 4,6-linked AGs. These cases were, in one instance, explained by an obsd. AmgRS-dependent expression of the MexXY multidrug efflux system, which accommodates a range of AGs, with RIF targeting of AmgRS undermining mexXY expression and its promotion of resistance to 4,5- and 4,6-linked AGs. Given this link between AmgRS, MexXY expression, and pan-AG resistance in P. aeruginosa, RIF might be a useful adjuvant in the AG treatment of P. aeruginosa infections.
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220. 220
  Mikalauskas, A., Parkins, M. D., and Poole, K. (2017) Rifampicin Potentiation of Aminoglycoside Activity against Cystic Fibrosis Isolates of Pseudomonas Aeruginosa. J. Antimicrob. Chemother. 72, 3349– 3352, DOI: 10.1093/jac/dkx296
  220
  Rifampicin potentiation of aminoglycoside activity against cystic fibrosis isolates of Pseudomonas aeruginosa
  Mikalauskas, Alaya; Parkins, Michael D.; Poole, Keith
  Journal of Antimicrobial Chemotherapy (2017), 72 (12), 3349-3352CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
  Objectives: Rifampicin potentiates the activity of aminoglycosides (AGs) vs. Pseudomonas aeruginosa by targeting the AmgRS two-component system. In this study we examine the impact of rifampicin on the AG susceptibility of cystic fibrosis (CF) lung isolates of P. aeruginosa and the contribution of AmgRS to AG resistance in these isolates. Methods:amgR deletion derivs. of clin. isolates were constructed using std. gene replacement technol. Susceptibility to AGs ± rifampicin (at 1/2 MIC) was assessed using a serial 2-fold diln. assay. Results: Rifampicin showed a variable ability to potentiate AG activity vs. the CF isolates, enhancing AG susceptibility between 2- and 128-fold. Most strains showed potentiation for at least two AGs, with only a few strains showing no AG potentiation by rifampicin. Notably, loss of amgR increased AG susceptibility although rifampicin potentiation of AG activity was still obsd. in the ΔamgR derivs. Conclusions: AmgRS contributes to AG resistance in CF isolates of P. aeruginosa and rifampicin shows a variable ability to potentiate AG activity against these, highlighting the complexity of AG resistance in such isolates.
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221. 221
  Docquier, J.-D. and Mangani, S. (2018) An Update on Beta-Lactamase Inhibitor Discovery and Development. Drug Resist. Updates 36, 13– 29, DOI: 10.1016/j.drup.2017.11.002
  221
  An update on β-lactamase inhibitor discovery and development
  Docquier Jean-Denis; Mangani Stefano
  Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy (2018), 36 (), 13-29 ISSN:.
  Antibiotic resistance, and the emergence of pan-resistant clinical isolates, seriously threatens our capability to treat bacterial diseases, including potentially deadly hospital-acquired infections. This growing issue certainly requires multiple adequate responses, including the improvement of both diagnosis methods and use of antibacterial agents, and obviously the development of novel antibacterial drugs, especially active against Gram-negative pathogens, which represent an urgent medical need. Considering the clinical relevance of both β-lactam antibiotics and β-lactamase-mediated resistance, the discovery and development of combinations including a β-lactamase inhibitor seems to be particularly attractive, despite being extremely challenging due to the enormous diversity, both structurally and mechanistically, of the potential β-lactamase targets. This review will cover the evolution of currently available β-lactamase inhibitors along with the most recent research leading to new β-lactamase inhibitors of potential clinical interest or already in the stage of clinical development.
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222. 222
  Chiem, K., Jani, S., Fuentes, B., Lin, D. L., Rasche, M. E., and Tolmasky, M. E. (2016) Identification of an Inhibitor of the Aminoglycoside 6’-N-Acetyltransferase Type Ib [AAC(6’)-Ib] by Glide Molecular Docking. MedChemComm 7, 184– 189, DOI: 10.1039/C5MD00316D
  222
  Identification of an inhibitor of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] by glide molecular docking
  Chiem, Kevin; Jani, Saumya; Fuentes, Brooke; Lin, David L.; Rasche, Madeline E.; Tolmasky, Marcelo E.
  MedChemComm (2016), 7 (1), 184-189CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  The aminoglycoside 6'-N-acetyltransferase type Ib, AAC(6')-Ib, confers resistance to clin. relevant aminoglycosides and is the most widely distributed enzyme among AAC(6')-I-producing Gram-neg. pathogens. An alternative to counter the action of this enzyme is the development of inhibitors. Glide is a computational strategy for rapidly docking ligands to protein sites and estg. their binding affinities. We docked a collection of 280 000 compds. from 7 sub-libraries of the Chembridge library as ligands to the aminoglycoside binding site of AAC(6')-Ib. We identified a compd., 1-[3-(2-aminoethyl)benzyl]-3-(piperidin-1-ylmethyl)pyrrolidin-3-ol (compd. 1), that inhibited the acetylation of aminoglycosides in vitro with IC50 values of 39.7 and 34.9 μM when the aminoglycoside substrates assayed were kanamycin A or amikacin, resp. The growth of an amikacin-resistant Acinetobacter baumannii clin. strain was inhibited in the presence of a combination of amikacin and compd. 1.
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223. 223
  Lomovskaya, O., Warren, M. S., Lee, A., Galazzo, J., Fronko, R., Lee, M., Blais, J., Cho, D., Chamberland, S., Renau, T., Leger, R., Hecker, S., Watkins, W., Hoshino, K., Ishida, H., and Lee, V. J. (2001) Identification and Characterization of Inhibitors of Multidrug Resistance Efflux Pumps in Pseudomonas Aeruginosa: Novel Agents for Combination Therapy. Antimicrob. Agents Chemother. 45, 105– 116, DOI: 10.1128/AAC.45.1.105-116.2001
  223
  Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy
  Lomovskaya, Olga; Warren, Mark S.; Lee, Angela; Galazzo, Jorge; Fronko, Richard; Lee, May; Blais, Johanne; Cho, Deidre; Chamberland, Suzanne; Renau, Tom; Leger, Roger; Hecker, Scott; Watkins, Will; Hoshino, Kazuki; Ishida, Hiroko; Lee, Ving J.
  Antimicrobial Agents and Chemotherapy (2001), 45 (1), 105-116CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  Whole-cell assays were implemented to search for efflux pump inhibitors (EPIs) of the three multidrug resistance efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN) that contribute to fluoroquinolone resistance in clin. isolates of Pseudomonas aeruginosa. Secondary assays were developed to identify lead compds. with exquisite activities as inhibitors. A broad-spectrum EPI which is active against all three known Mex efflux pumps from P. aeruginosa and their close Escherichia coli efflux pump homol. (AcrAB-TolC) was discovered. When this compd., MC-207,110 (I), was used, the intrinsic resistance of P. aeruginosa to fluoroquinolones was decreased significantly (eight-fold for levofloxacin). Acquired resistance due to the overexpression of efflux pumps was also decreased (32- to 64-fold redn. in the MIC of levofloxacin). Similarly, 32- to 64-fold redns. in MICs in the presence of I were obsd. for strains with overexpressed efflux pumps and various target mutations that confer resistance to levofloxacin (e.g., gyrA and parC). We also compared the frequencies of emergence of levofloxacin-resistant variants in the wild-type strain at four times the MIC of levofloxacin (1 μg/mL) when it was used either alone or in combination with EPI. In the case of levofloxacin alone, the frequency was ∼10-7 CFU/mL. In contrast, with an EPI, the frequency was below the level of detection (<10-11). In summary, we have demonstrated that inhibition of efflux pumps (i) decreased the level of intrinsic resistance significantly, (ii) reversed acquired resistance, and (iii) resulted in a decreased frequency of emergence of P. aeruginosa strains that are highly resistant to fluoroquinolones.
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224. 224
  Gupta, S., Cohen, K. A., Winglee, K., Maiga, M., Diarra, B., and Bishai, W. R. (2014) Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium Tuberculosis. Antimicrob. Agents Chemother. 58, 574– 576, DOI: 10.1128/AAC.01462-13
  224
  Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis
  Gupta, Shashank; Cohen, Keira A.; Winglee, Kathryn; Maiga, Mamoudou; Diarra, Bassirou; Bishai, William R.
  Antimicrobial Agents and Chemotherapy (2014), 58 (1), 574-576, 4 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Drug efflux is an important resistance mechanism in Mycobacterium tuberculosis. We found that verapamil, an efflux inhibitor, profoundly decreases the MIC of bedaquiline and clofazimine to M. tuberculosis by 8- to 16-fold. This exquisite susceptibility was noted among drug-susceptible and drug-resistant clin. isolates. Thus, efflux inhibition is an important sensitizer of bedaquiline and clofazimine, and efflux may emerge as a resistance mechanism to these drugs.
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225. 225
  Singh, M., Jadaun, G. P. S., Ramdas Srivastava, K., Chauhan, V., Mishra, R., Gupta, K., Nair, S., Chauhan, D. S., Sharma, V. D., Venkatesan, K., and Katoch, V. M. (2011) Effect of Efflux Pump Inhibitors on Drug Susceptibility of Ofloxacin Resistant Mycobacterium Tuberculosis Isolates. Indian J. Med. Res. 133, 535– 540
  225
  Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates
  Singh, Mradula; Jadaun, G. P. S.; Ramdas; Srivastava, K.; Chauhan, Vipin; Mishra, Ritu; Gupta, Kavita; Nair, Surya; Chauhan, D. S.; Sharma, V. D.; Venkatesan, K.; Katoch, V. M.
  Indian Journal of Medical Research (2011), 133 (5), 535-540CODEN: IMIREV; ISSN:0971-5916. (Indian Council of Medical Research)
  In drug resistant, esp. multi-drug resistant (MDR) tuberculosis, fluoroquinolones (FQs) are used as second line drugs. However, the incidence of FQ-resistant Mycobacterium tuberculosis is rapidly increasing which may be due to extensive use of FQs in the treatment of various other diseases. The most important known mechanism i.e., gyrA mutation in FQ resistance is not obsd. in a significant proportion of FQ resistant M. tuberculosis isolates suggesting that the resistance may be because of other mechanisms such as an active drug efflux pump. In this study we evaluated the role of the efflux pumps in quinolone resistance by using various inhibitors such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP), 2,4-dinitrophenol (DNP) and verapamil, in clin. isolates of M. tuberculosis. A total of 55 M. tuberculosis clin. isolates [45 ofloxacin (OFL) resistant and 10 ofloxacin sensitive] were tested by Resazurin microtiter assay (REMA) to observe the changes in ofloxacin min. inhibitory concn. (MIC) levels in presence of efflux inhibitors as compared to control (without efflux inhibitor). The MIC levels of OFL showed 2-8 folds redn. in presence of CCCP (16/45; 35.5%), verapamil (24/45; 53.3%) and DNP (21/45; 46.6%) while in case of isolates identified as OFL sensitive these did not show any effect on ofloxacin MICs. In 11 of 45 (24.5%) isolates change in MIC levels was obsd. with all the three inhibitors. Overall 30 (66.6%) isolates had redn. in OFL MIC after treatment with these inhibitors. A total of eight isolates were sequenced for gyrA gene, of which, seven (87.5%) showed known mutations. Of the eight sequenced isolates, seven (87.5%) showed 2 to 8 fold change in MIC in presence of efflux inhibitors. Our findings suggest the involvement of active efflux pumps of both Major Facilitator Super Family (MFS) family (inhibited by CCCP and DNP) and ATP Binding Cassette (ABC) transporters (inhibited by verapamil) in the development of OFL resistance in M. tuberculosis isolates. Epidemiol. significance of these findings needs to be detd. in prospective studies with appropriate no. of samples / isolates.
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226. 226
  Hogg, G. M., Barr, J. G., and Webb, C. H. (1998) In-Vitro Activity of the Combination of Colistin and Rifampicin against Multidrug-Resistant Strains of Acinetobacter Baumannii. J. Antimicrob. Chemother. 41, 494– 450, DOI: 10.1093/jac/41.4.494
  226
  In vitro activity of the combination of colistin and rifampicin against multidrug-resistant strains of Acinetobacter baumannii
  Hogg, G. M.; Barr, J. G.; Webb, C. H.
  Journal of Antimicrobial Chemotherapy (1998), 41 (4), 494-495CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  The authors have demonstrated, by in vitro studies, the theor. value of the combination of colistin and rifampicin as treatment for patients with infections caused by drug-resistant A. baumannii.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXisV2qu7Y%253D&md5=61fa9d8488d4e937e2a97a16cae4fe5b
227. 227
  MacGowan, A. P., Rynn, C., Wootton, M., Bowker, K. E., Holt, H. A., Reeves, D. S. (1999) In Vitro Assessment of Colistin’s Antipseudomonal Antimicrobial Interactions with Other Antibiotics. Clin. Microbiol. Infect. 5, 32– 36, DOI: 10.1111/j.1469-0691.1999.tb00095.x
  227
  In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics
  MacGowan, Alasdair P.; Rynn, Caroline; Wootton, Mandy; Bowker, Karen E.; Holt, H. Alan; Reeves, David S.
  Clinical Microbiology and Infection (1999), 5 (1), 32-36CODEN: CMINFM; ISSN:1198-743X. (Decker Europe)
  The objective of this study was to examine the interactions of colistin (MIC 2 mg/L) at concns. of 0.5 and 5 mg/L with ceftazidime (1 and 75 mg/L, MIC 0.5 mg/L), aztreonam (1 and 30 mg/L, MIC 0.12 mg/L), meropenem (1 and 25 mg/L, MIC 0.03 mg/L), gentamicin (1 and 10 mg/L, MIC 2 mg/L), piperacillin (5 and 100 mg/L, MIC 4 mg/L) and ciprofloxacin (0.25 and 4 mg/L, MIC 1 mg/L) using a representative strain of Pseudomonas aeruginosa isolated from a cystic fibrosis patient. The method used was a bacterial time kill curve with single agents and combinations. Using inocula of 106 CFU/mL, multiple sampling was performed over 6 h and in triplicate. The AUBKC of the time vs. viable count curve, with single agents and combinations of agents, was taken as the endpoint for comparison. For colistin plus ceftazidime, colistin plus aztreonam, colistin plus meropenem and colistin plus ciprofloxacin, the pattern was for all the combinations (high or low concns.) to produce smaller AUBKCs than single agents. In expts. using a bacteriostatic agent such as ceftazidime, the AUBKCs (log CFU/μL per h) for colistin 0.5 mg/L or 5 mg/L alone were 32.3±0.8 or 12.7±0.5, and for ceftazidime 1 mg/L or 75 mg/L alone they were 24.3±1.5 or 20.9±2.7. Combinations of colistin 0.5 mg/L plus either ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 23.8±1.8 or 16.1 mg/L. Combinations of colistin 5 mg/L plus ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 12.2±0.8 or 8.7±1.0. The AUBKCs for colistin 5 mg/L plus 75 mg/L are significantly smaller than those for the single agents, indicating synergy. In expts. using the bactericidal agent ciprofloxacin, the AUBKCs (log CFU/mL per h) for colistin 0.5 mg/L or 5 mg/L alone were 33.6±1.9 or 11.2±2.4, and for ciprofloxacin 0.25 mg/L or 4 mg/L alone they were 32.8±1.3 or 5.0±0.7. Combinations of colistin 0.5 mg/L plus either ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 32.2±0.9 or 4.3±1.4. Combinations of colistin 5 mg/L plus ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 10.7±1.5 or 4.2±0.6. Although combination AUBKCs were smaller than those for single agents, in no case did this reach statistical significance (p<0.05). These studies indicate that addn. of colistin to other antipseudomonal drugs tends to produce smaller AUBKCs and hence greater killing of Pseudomonas aeruginosa than monotherapy.
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228. 228
  Petrosillo, N., Chinello, P., Proietti, M. F., Cecchini, L., Masala, M., Franchi, C., Venditti, M., Esposito, S., and Nicastri, E. (2005) Combined Colistin and Rifampicin Therapy for Carbapenem-Resistant Acinetobacter Baumannii Infections: Clinical Outcome and Adverse Events. Clin. Microbiol. Infect. 11, 682– 683, DOI: 10.1111/j.1469-0691.2005.01198.x
  228
  Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii infections: clinical outcome and adverse events
  Petrosillo, N.; Chinello, P.; Proietti, M. F.; Cecchini, L.; Masala, M.; Franchi, C.; Venditti, M.; Esposito, S.; Nicastri, E.
  Clinical Microbiology and Infection (2005), 11 (8), 682-683CODEN: CMINFM; ISSN:1198-743X. (Blackwell Publishing Ltd.)
  Fourteen critically-ill patients with carbapenem-resistant Acinetobacter baumannii infections (mean age 49 years), in the intensive care units of three urban hospitals in Rome, Italy were studied. Therapy with colistin-rifampicin, and with ampicillin-sulbactam in case of susceptibility to this combination, resulted in microbiol. clearance of carbapenem-resistant A. baumannii infection in nine (64%) of these 14 patients, with limited side-effects.
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229. 229
  Kerrigan, J. E., Ragunath, C., Kandra, L., Gyemant, G., Liptak, A., Janossy, L., Kaplan, J. B., and Ramasubbu, N. (2008) Modeling and Biochemical Analysis of the Activity of Antibiofilm Agent Dispersin B. Acta Biol. Hung. 59, 439– 451, DOI: 10.1556/ABiol.59.2008.4.5
  229
  Modeling and biochemical analysis of the activity of antibiofilm agent Dispersin B
  Kerrigan J E; Ragunath C; Kandra Lili; Gyemant Gyongyi; Liptak A; Janossy L; Kaplan J B; Ramasubbu N
  Acta biologica Hungarica (2008), 59 (4), 439-51 ISSN:0236-5383.
  Bacteria in a biofilm are enmeshed in a self-synthesized extracellular polysaccharide matrix (PGA), which is a linear polymer of beta(1,6)-linked N-acetylglucosamine (GlcNAc) residues. Dispersin B (DspB), a soluble glycoside hydrolase produced by the periodontal pathogen Actinobacillus actinomycetemcomitans degrades PGA. The enzyme DspB is an alpha/beta TIM-barrel protein and belongs to family 20 glycosyl hydrolases members. The enzyme activity of DspB with regard to its substrate specificity towards beta(1,6)-linked GlcNAc polymers and its endo/exo character was investigated through ligand docking and the hydrolysis of synthetic oligosaccharides. Ligand docking analysis suggested that beta(1,6)-linked GlcNAc oligosaccharide bound to the active site better that beta(1,4)-linked GlcNAc oligosaccharide. Our combined results indicate that DspB is an exo-acting enzyme that hydrolyzes beta(1,6)-linked N-acetylglucosamine oligomers.
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230. 230
  Ramasubbu, N., Thomas, L. M., Ragunath, C., and Kaplan, J. B. (2005) Structural Analysis of Dispersin B, a Biofilm-Releasing Glycoside Hydrolase from the Periodontopathogen Actinobacillus Actinomycetemcomitans. J. Mol. Biol. 349, 475– 486, DOI: 10.1016/j.jmb.2005.03.082
  230
  Structural Analysis of Dispersin B, a Biofilm-releasing Glycoside Hydrolase from the Periodontopathogen Actinobacillus actinomycetemcomitans
  Ramasubbu, N.; Thomas, L. M.; Ragunath, C.; Kaplan, J. B.
  Journal of Molecular Biology (2005), 349 (3), 475-486CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)
  Bacteria in a biofilm are enmeshed in a self-synthesized extracellular polysaccharide matrix that holds the bacteria together in a mass and firmly attaches the bacterial mass to the underlying surface. A major component of the extracellular polysaccharide matrix in several phylogenetically diverse bacteria is PGA, a linear polymer of N-acetylglucosamine residues in β(1,6)-linkage. PGA is produced by the Gram-neg. periodontopathogen Actinobacillus actinomycetemcomitans as well as by the Gram-pos. device-assocd. pathogen Staphylococcus epidermidis. We recently reported that A. actinomycetemcomitans produces a sol. glycoside hydrolase named dispersin B, which degrades PGA. Here, we present the crystal structure of dispersin B at 2.0 Å in complex with a glycerol and an acetate ion at the active site. The enzyme crystallizes in the orthorhombic space group C2221 with cell dimensions a=41.02 Å, b=86.13 Å, c=185.77 Å. The core of the enzyme consists a (β/α)8 barrel topol. similar to other β-hexosaminidases but significant differences exist in the arrangement of loops hovering in the vicinity of the active site. The location and interactions of the glycerol and acetate moieties in conjunction with the sequence anal. suggest that dispersin B cleaves β(1,6)-linked N-acetylglucosamine polymer using a catalytic machinery similar to other family 20 hexosaminidases which cleave β(1,4)-linked N-acetylglucosamine residues.
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231. 231
  Brindle, E. R., Miller, D. A., and Stewart, P. S. (2011) Hydrodynamic Deformation and Removal of Staphylococcus Epidermidis Biofilms Treated with Urea, Chlorhexidine, Iron Chloride, or DispersinB. Biotechnol. Bioeng. 108, 2968– 2977, DOI: 10.1002/bit.23245
  231
  Hydrodynamic deformation and removal of Staphylococcus epidermidis biofilms treated with urea, chlorhexidine, iron chloride, or DispersinB
  Brindle, Eric R.; Miller, David A.; Stewart, Philip S.
  Biotechnology and Bioengineering (2011), 108 (12), 2968-2977CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)
  The force-deflection and removal characteristics of bacterial biofilm were measured by two different techniques before and after chem., or enzymic, treatment. The first technique involved time lapse imaging of a biofilm grown in a capillary flow cell and subjected to a brief shear stress challenge imparted through increased fluid flow. Biofilm removal was detd. by calcg. the redn. in biofilm area from quant. anal. of transmission images. The second technique was based on micro-indentation using an at. force microscope. In both cases, biofilms formed by Staphylococcus epidermidis were exposed to buffer (untreated control), urea, chlorhexidine, iron chloride, or DispersinB. In control expts., the biofilm exhibited force-deflection responses that were similar before and after the same treatment. The biofilm structure was stable during the post-treatment shear challenge (1% loss). Biofilms treated with chlorhexidine became less deformable after treatment and no increase in biomass removal was seen during the post-treatment shear challenge (2% loss). In contrast, biofilms treated with urea or DispersinB became more deformable and exhibited significant biofilm loss during the post-treatment flow challenge (71% and 40%, resp.). During the treatment soak phase, biofilms exposed to urea swelled. Biofilms exposed to iron chloride showed little difference from the control other than slight contraction during the treatment soak. These observations suggest the following interpretations: (1) chem. or enzymic treatments, including those that are not frankly antimicrobial, can alter the cohesion of bacterial biofilm; (2) biocidal treatments (e.g., chlorhexidine) do not necessarily weaken the biofilm; and (3) biofilm removal following treatment with agents that make the biofilm more deformable (e.g., urea, DispersinB) depend on interaction between the moving fluid and the biofilm structure. Measurements such as those reported here open the door to development of new technologies for controlling detrimental biofilms by targeting biofilm cohesion rather than killing microorganisms.
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232. 232
  Fernandez-Lopez, R., Machon, C., Longshaw, C. M., Martin, S., Molin, S., Zechner, E. L., Espinosa, M., Lanka, E., and de la Cruz, F. (2005) Unsaturated Fatty Acids Are Inhibitors of Bacterial Conjugation. Microbiology 151, 3517– 3526, DOI: 10.1099/mic.0.28216-0
  232
  Unsaturated fatty acids are inhibitors of bacterial conjugation
  Fernandez-Lopez, Raul; Machon, Cristina; Longshaw, Christopher M.; Martin, Steve; Molin, Soren; Zechner, Ellen L.; Espinosa, Manuel; Lanka, Erich; de la Cruz, Fernando
  Microbiology (Reading, United Kingdom) (2005), 151 (11), 3517-3526CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
  This report describes a high-throughput assay to identify substances that reduce the frequency of conjugation in Gram-neg. bacteria. Bacterial conjugation is largely responsible for the spread of multiple antibiotic resistances in human pathogens. Conjugation inhibitors may provide a means to control the spread of antibiotic resistance. An automated conjugation assay was developed that used plasmid R388 and a lab. strain of Escherichia coli as a model system, and bioluminescence as a reporter for conjugation activity. Frequencies of conjugation could be measured continuously in real time by the amt. of light produced, and thus the effects of inhibitory compds. could be detd. quant. A control assay, run in parallel, allowed elimination of compds. affecting cell growth, plasmid stability or gene expression. The automated conjugation assay was used to screen a database of more than 12 000 microbial exts. known to contain a wide variety of bioactive compds. (the NatChem library). The initial hit rate was 1.4%. From these, 48 exts. contg. active compds. and representing a variety of organisms and extn. conditions were subjected to fractionation (24 fractions per ext.). The 52 most active fractions were subjected to a secondary anal. to det. the range of plasmid inhibition. Plasmids R388, R1 and RP4 were used as representatives of a variety of plasmid transfer systems. Only one fraction (of complex compn.) affected transfer of all three plasmids, while four other fractions were active against two of them. Two sep. compds. were identified from these fractions: linoleic acid and dehydrocrepenynic acid. Downstream anal. showed that the chem. class of unsatd. fatty acids act as true inhibitors of conjugation.
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233. 233
  Perry, J. A., Koteva, K., Verschoor, C. P., Wang, W., Bowdish, D. M. E., and Wright, G. D. (2015) A Macrophage-Stimulating Compound from a Screen of Microbial Natural Products. J. Antibiot. 68, 40– 46, DOI: 10.1038/ja.2014.83
  233
  A macrophage-stimulating compound from a screen of microbial natural products
  Perry, Julie A.; Koteva, Kalinka; Verschoor, Chris P.; Wang, Wenliang; Bowdish, Dawn ME; Wright, Gerry D.
  Journal of Antibiotics (2015), 68 (1), 40-46CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
  Rising rates of antibiotic resistance in bacterial pathogens is a medical crisis of global concern that necessitates the development of new treatment strategies. We have isolated a natural product with macrophage-stimulating activity from a screen of microbially produced bioactive mols. Streptazolin increased bacterial killing and elaboration of immunostimulatory cytokines by macrophages in vitro. Furthermore, we show that streptazolin stimulates the macrophage nuclear factor κB (NF-κB) pathway via phosphatidylinositide 3-kinase (PI3K) signaling, and that the conjugated diene moiety is essential for stimulatory activity. Immunostimulatory mols. like streptazolin represent entries into new treatment paradigms to address the challenge of antibiotic resistance.
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234. 234
  Gonzalez-Bello, C., Rodriguez, D., Pernas, M., Rodriguez, A., and Colchon, E. (2020) Beta-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against Superbugs. J. Med. Chem. 63, 1859, DOI: 10.1021/acs.jmedchem.9b01279
  234
  β-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against Superbugs
  Gonzalez-Bello, Concepcion; Rodriguez, Diana; Pernas, Marina; Rodriguez, Angela; Colchon, Esther
  Journal of Medicinal Chemistry (2020), 63 (5), 1859-1881CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Infections caused by resistant bacteria are nowadays too common and some pathogens have even become resistant to multiple types of antibiotics, in which cases few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy 'antibiotic + inhibitor of resistance'. These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clin. use. Three main types of compds. have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; and (iii) efflux pump inhibitors. This perspective article is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-neg. bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems and monobactams), by the prodn. of β-lactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.
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235. 235
  Drawz, S. M. and Bonomo, R. A. (2010) Three Decades of β-Lactamase Inhibitors. Clin. Microbiol. Rev. 23, 160– 201, DOI: 10.1128/CMR.00037-09
  235
  Three decades of β-lactamase inhibitors
  Drawz, Sarah M.; Bonomo, Robert A.
  Clinical Microbiology Reviews (2010), 23 (1), 160-201CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
  A review. Since the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clin. practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clin. relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clin. and microbiol. features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compds. and the chem. features of these agents that may contribute to a "second generation" of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.
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236. 236
  Garneau-Tsodikova, S. and Labby, K. J. (2016) Mechanisms of Resistance to Aminoglycoside Antibiotics: Overview and Perspectives. MedChemComm 7, 11– 27, DOI: 10.1039/C5MD00344J
  236
  Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives
  Garneau-Tsodikova, Sylvie; Labby, Kristin J.
  MedChemComm (2016), 7 (1), 11-27CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  A review. Aminoglycoside (AG) antibiotics are used to treat many Gram-neg. and some Gram-pos. infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small mols. such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clin. prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clin. relevance.
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237. 237
  Li, Y., Green, K. D., Johnson, B. R., and Garneau-Tsodikova, S. (2015) Inhibition of Aminoglycoside Acetyltransferase Resistance Enzymes by Metal Salts. Antimicrob. Agents Chemother. 59, 4148– 4156, DOI: 10.1128/AAC.00885-15
  237
  Inhibition of aminoglycoside acetyltransferase resistance enzymes by metal salts
  Li, Yijia; Green, Keith D.; Johnson, Brooke R.; Garneau-Tsodikova, Sylvie
  Antimicrobial Agents and Chemotherapy (2015), 59 (7), 4148-4156CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  Aminoglycosides (AGs) are clin. relevant antibiotics used to treat infections caused by both Gram-neg. and Gram-pos. bacteria, as well as Mycobacteria. As with all current antibacterial agents, resistance to AGs is an increasing problem. The most common mechanism of resistance to AGs is the presence of AG-modifying enzymes (AMEs) in bacterial cells, with AG acetyltransferases (AACs) being the most prevalent. Recently, it was discovered that Zn2+ metal ions displayed an inhibitory effect on the resistance enzyme AAC(6')-Ib in Acinetobacter baumannii and Escherichia coli. In this study, we explore a wide array of metal salts (Mg2+, Cr3+, Cr6+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Au3+ with different counter ions) and their inhibitory effect on a large repertoire of AACs [AAC(2')-Ic, AAC(3)-Ia, AAC(3)-Ib, AAC(3)-IV, AAC(6')-Ib', AAC(6')-Ie, AAC(6')-IId, and Eis]. In addn., we det. the MIC values for amikacin and tobramycin in combination with a zinc pyrithione complex in clin. isolates of various bacterial strains (two strains of A. baumannii, three of Enterobacter cloacae, and four of Klebsiella pneumoniae) and one representative of each species purchased from the American Type Culture Collection.
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238. 238
  Lin, D. L., Tran, T., Adams, C., Alam, J. Y., Herron, S. R., and Tolmasky, M. E. (2013) Inhibitors of the Aminoglycoside 6’-N-Acetyltransferase Type Ib [AAC(6’)-Ib] Identified by in Silico Molecular Docking. Bioorg. Med. Chem. Lett. 23, 5694– 5698, DOI: 10.1016/j.bmcl.2013.08.016
  238
  Inhibitors of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] identified by in silico molecular docking
  Lin, David L.; Tran, Tung; Adams, Christina; Alam, Jamal Y.; Herron, Steven R.; Tolmasky, Marcelo E.
  Bioorganic & Medicinal Chemistry Letters (2013), 23 (20), 5694-5698CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  AAC(6')-Ib is an important aminoglycoside resistance enzyme to target with enzymic inhibitors. An in silico screening approach was used to identify potential inhibitors from the ChemBridge library. Several compds. were identified, of which two of them, 4-[(2-{[1-(3-methylphenyl)-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene]methyl}phenoxy)methyl]benzoic acid and 2-{5-[(4,6-dioxo-1,3-diphenyl-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid, showed micromolar activity in inhibiting acetylation of kanamycin A. These compds. are predicted to bind the aminoglycoside binding site of AAC(6')-Ib and exhibited competitive inhibition against kanamycin A.
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239. 239
  Green, K. D., Chen, W., and Garneau-Tsodikova, S. (2012) Identification and Characterization of Inhibitors of the Aminoglycoside Resistance Acetyltransferase Eis from Mycobacterium Tuberculosis. ChemMedChem 7, 73– 77, DOI: 10.1002/cmdc.201100332
  239
  Identification and Characterization of Inhibitors of the Aminoglycoside Resistance Acetyltransferase Eis from Mycobacterium tuberculosis
  Green, Keith D.; Chen, Wenjing; Garneau-Tsodikova, Sylvie
  ChemMedChem (2012), 7 (1), 73-77CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Inhibitors of aminoglycoside resistance acetyltransferase Eis from Mycobacterium tuberculosis were identified by high throughput screening.
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240. 240
  Li, X.-Z., Plesiat, P., and Nikaido, H. (2015) The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria. Clin. Microbiol. Rev. 28, 337– 418, DOI: 10.1128/CMR.00117-14
  240
  The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria
  Li, Xian-Zhi; Plesiat, Patrick; Nikaido, Hiroshi
  Clinical Microbiology Reviews (2015), 28 (2), 337-418CODEN: CMIREX; ISSN:1098-6618. (American Society for Microbiology)
  The global emergence of multidrug-resistant Gram-neg. bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clin. relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Addnl., efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technol. advances have allowed for an in-depth understanding of the structural and biochem. basis, substrate profiles, mol. regulation, and inhibition of MDR pumps. However, the development of clin. useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clin. significance, together with methodol. considerations for the characterization of MDR pumps.
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241. 241
  Sharma, A., Gupta, V. K., and Pathania, R. (2019) Efflux Pump Inhibitors for Bacterial Pathogens: From Bench to Bedside. Indian J. Med. Res. 149, 129– 145, DOI: 10.4103/ijmr.IJMR_2079_17
  241
  Efflux pump inhibitors for bacterial pathogens: From bench to bedside
  Sharma, Atin; Gupta, Vivek Kumar; Pathania, Ranjana
  Indian Journal of Medical Research (2019), 149 (2), 129-145CODEN: IMIREV ISSN:. (Medknow Publications)
  A review. With the advent of antibiotics, bacterial infections were supposed to be a thing of past. However, this instead led to the selection and evolution of bacteria with mechanisms to counter the action of antibiotics. Antibiotic efflux is one of the major mechanisms, whereby bacteria pump out the antibiotics from their cellular interior to the external environment using special transporter proteins called efflux pumps. Inhibiting these pumps seems to be an attractive strategy at a time when novel antibiotic supplies are dwindling. Mols. capable of inhibiting these pumps, known as efflux pump inhibitors (EPIs), have been viewed as potential therapeutic agents that can rejuvenate the activity of antibiotics that are no longer effective against bacterial pathogens. EPIs follow some general mechanisms of efflux inhibition and are derived from various natural as well as synthetic sources. This review focuses on EPIs and identifies the challenges that have kept these futuristic therapeutics away from the com. realm so far.
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242. 242
  Handzlik, J., Matys, A., and Kieć-Kononowicz, K. (2013) Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. Aureus. Antibiotics 2, 28– 45, DOI: 10.3390/antibiotics2010028
  242
  Recent advances in multi-drug resistance (MDR) efflux pump inhibitors of Gram-positive bacteria S. aureus
  Handzlik, Jadwiga; Matys, Anna; Kiec-Kononowicz, Katarzyna
  Antibiotics (Basel, Switzerland) (2013), 2 (1), 28-45CODEN: ABSNC4; ISSN:2079-6382. (MDPI AG)
  A review. The paper focuses on recent achievements in the search for new chem. compds. able to inhibit multidrug resistance (MDR) mechanisms in Gram-pos. pathogens. An anal. of the results of the search for new efflux pump inhibitors (EPIs) for Gram-pos. bacteria, which have been performed over the last decade, indicates that almost all efforts are focused on the NorA (MFS) efflux pump in S. aureus. Considering the chem. structures of the NorA EPIs that have been identified, it can be obsd. that the most active agents belong to the families of compds. possessing conjugated double bonds, e.g., chalcones, piperine-like compds., N-cinnamoylphenalkylamides or citral amide derivs. Indole-, dihydronaphthyl-, 2-chloro-5-bromo-phenyl- or piperidine moieties seem to be profitable for the EPI properties, as well. These results, together with an increasing knowledge about a variety of efflux pumps that are involved in MDR of Gram-pos. pathogens underline that further search for new EPIs should pay more attention to develop MDR efflux protein targets, including SMR, MATE, ABC or other members of the MFS family.
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243. 243
  Spengler, G., Kincses, A., Gajdacs, M., and Amaral, L. (2017) New Roads Leading to Old Destinations: Efflux Pumps as Targets to Reverse Multidrug Resistance in Bacteria. Molecules 22, 468, DOI: 10.3390/molecules22030468
  243
  New roads leading to old destinations: efflux pumps as targets to reverse multidrug resistance in bacteria
  Spengler, Gabriella; Kincses, Annamaria; Gajdacs, Mario; Amaral, Leonard
  Molecules (2017), 22 (3), 468/1-468/25CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  A review. Multidrug resistance (MDR) has appeared in response to selective pressures resulting from the incorrect use of antibiotics and other antimicrobials. This inappropriate application and mismanagement of antibiotics have led to serious problems in the therapy of infectious diseases. Bacteria can develop resistance by various mechanisms and 1 of the most important factors resulting in MDR is efflux pump-mediated resistance. Because of the importance of the efflux-related multidrug resistance the development of new therapeutic approaches aiming to inhibit bacterial efflux pumps is a promising way to combat bacteria having over-expressed MDR efflux systems. The definition of an efflux pump inhibitor (EPI) includes the ability to render the bacterium increasingly more sensitive to a given antibiotic or even reverse the multidrug resistant phenotype. In the recent years numerous EPIs have been developed, although so far their clin. application has not yet been achieved due to their in vivo toxicity and side effects. We aim to give a short overview of efflux-mediated resistance in bacteria, EPI compds. of plant and synthetic origin, and the possible methods to investigate and screen EPI compds. in bacterial systems.
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244. 244
  Song, L. and Wu, X. (2016) Development of Efflux Pump Inhibitors in Antituberculosis Therapy. Int. J. Antimicrob. Agents 47, 421– 429, DOI: 10.1016/j.ijantimicag.2016.04.007
  244
  Development of efflux pump inhibitors in antituberculosis therapy
  Song, Lele; Wu, Xueqiong
  International Journal of Antimicrobial Agents (2016), 47 (6), 421-429CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
  Resistance and tolerance to antituberculosis (anti-TB) drugs, esp. the first-line drugs, has become a serious problem in anti-TB therapy. Efflux of antimicrobial agents via bacterial efflux pumps is one of the main reasons for drug resistance. Efflux pump inhibitors (EPIs) bind to efflux pumps to inhibit drug efflux and thus enhance the drug effect and reduce drug resistance. Studies on EPIs targeting the efflux pumps of Mycobacterium tuberculosis (Mtb) help to understand Mtb resistance and to identify the potential drug target and are of significance in guiding the development of new anti-TB drugs and optimal combinations. Currently, there are many potential EPIs under study, but none of them has been used clin. for anti-TB therapy. In this article, we will provide an overview on the current development of EPIs targeting the efflux pumps of Mtb and discuss their potential clin. applications.
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  Schillaci, D., Spano, V., Parrino, B., Carbone, A., Montalbano, A., Barraja, P., Diana, P., Cirrincione, G., and Cascioferro, S. (2017) Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms. J. Med. Chem. 60, 8268– 8297, DOI: 10.1021/acs.jmedchem.7b00215
  245
  Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms
  Schillaci, Domenico; Spano, Virginia; Parrino, Barbara; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo; Cascioferro, Stella
  Journal of Medicinal Chemistry (2017), 60 (20), 8268-8297CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chem. agents that target the most common mechanisms of antibiotic resistance such as enzymic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here the authors assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. The authors also discuss the potential clin. application of chem. inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymic inhibitors, such as the derivs. of the β-lactamase inhibitor avibactam, are closer to the clinic than other mols. For example, MK-7655, in combination with imipenem, is in clin. development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addn., other mols. targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.
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246. 246
  Soucy, S. M., Huang, J., and Gogarten, J. P. (2015) Horizontal Gene Transfer: Building the Web of Life. Nat. Rev. Genet. 16, 472– 482, DOI: 10.1038/nrg3962
  246
  Horizontal gene transfer: building the web of life
  Soucy, Shannon M.; Huang, Jinling; Gogarten, Johann Peter
  Nature Reviews Genetics (2015), 16 (8), 472-482CODEN: NRGAAM; ISSN:1471-0056. (Nature Publishing Group)
  A review. Horizontal gene transfer (HGT) is the sharing of genetic material between organisms that are not in a parent-offspring relationship. HGT is a widely recognized mechanism for adaptation in bacteria and archaea. Microbial antibiotic resistance and pathogenicity are often assocd. with HGT, but the scope of HGT extends far beyond disease-causing organisms. In this review, we describe how HGT has shaped the web of life using examples of HGT among prokaryotes, between prokaryotes and eukaryotes, and even between multicellular eukaryotes. We discuss replacement and additive HGT, the proposed mechanisms of HGT, selective forces that influence HGT, and the evolutionary impact of HGT on ancestral populations and existing populations such as the human microbiome.
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  Graf, F. E., Palm, M., Warringer, J., and Farewell, A. (2019) Inhibiting Conjugation as a Tool in the Fight against Antibiotic Resistance. Drug Dev. Res. 80, 19– 23, DOI: 10.1002/ddr.21457
  247
  Inhibiting conjugation as a tool in the fight against antibiotic resistance
  Graf, Fabrice E.; Palm, Martin; Warringer, Jonas; Farewell, Anne
  Drug Development Research (2019), 80 (1), 19-23CODEN: DDREDK; ISSN:0272-4391. (Wiley-Liss, Inc.)
  Hit, Lead & Candidate Discovery Antibiotic resistance, esp. in gram-neg. bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addn. to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.
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  Cabezón, E., de la Cruz, F., and Arechaga, I. (2017) Conjugation Inhibitors and Their Potential Use to Prevent Dissemination of Antibiotic Resistance Genes in Bacteria. Front. Microbiol. 8, 2329, DOI: 10.3389/fmicb.2017.02329
  248
  Conjugation Inhibitors and Their Potential Use to Prevent Dissemination of Antibiotic Resistance Genes in Bacteria
  Cabezon Elena; de la Cruz Fernando; Arechaga Ignacio
  Frontiers in microbiology (2017), 8 (), 2329 ISSN:1664-302X.
  Antibiotic resistance has become one of the most challenging problems in health care. Bacteria conjugation is one of the main mechanisms whereby bacteria become resistant to antibiotics. Therefore, the search for specific conjugation inhibitors (COINs) is of interest in the fight against the spread of antibiotic resistances in a variety of laboratory and natural environments. Several compounds, discovered as COINs, are promising candidates in the fight against plasmid dissemination. In this review, we survey the effectiveness and toxicity of the most relevant compounds. Particular emphasis has been placed on unsaturated fatty acid derivatives, as they have been shown to be efficient in preventing plasmid invasiveness in bacterial populations. Biochemical and structural studies have provided insights concerning their potential molecular targets and inhibitory mechanisms. These findings open a new avenue in the search of new and more effective synthetic inhibitors. In this pursuit, the use of structure-based drug design methods will be of great importance for the screening of ligands and binding sites of putative targets.
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249. 249
  Getino, M., Sanabria-Rios, D. J., Fernandez-Lopez, R., Campos-Gomez, J., Sanchez-Lopez, J. M., Fernandez, A., Carballeira, N. M., and de la Cruz, F. (2015) Synthetic Fatty Acids Prevent Plasmid-Mediated Horizontal Gene Transfer. mBio 6, e01032-15 DOI: 10.1128/mBio.01032-15
  There is no corresponding record for this reference.
250. 250
  Zhu, L. and Lau, G. W. (2011) Inhibition of Competence Development, Horizontal Gene Transfer and Virulence in Streptococcus Pneumoniae by a Modified Competence Stimulating Peptide. PLoS Pathog. 7, e1002241 DOI: 10.1371/journal.ppat.1002241
  250
  Inhibition of competence development, horizontal gene transfer and virulence in Streptococcus pneumoniae by a modified competence stimulating peptide
  Zhu, Luchang; Lau, Gee W.
  PLoS Pathogens (2011), 7 (9), e1002241CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  Competence stimulating peptide (CSP) is a 17-amino acid peptide pheromone secreted by Streptococcus pneumoniae. Upon binding of CSP to its membrane-assocd. receptor kinase ComD, a cascade of signaling events is initiated, leading to activation of the competence regulon by the response regulator ComE. Genes encoding proteins that are involved in DNA uptake and transformation, as well as virulence, are upregulated. Previous studies have shown that disruption of key components in the competence regulon inhibits DNA transformation and attenuates virulence. Thus, synthetic analogs that competitively inhibit CSPs may serve as attractive drugs to control pneumococcal infection and to reduce horizontal gene transfer during infection. The authors performed amino acid substitutions on conserved amino acid residues of CSP1 in an effort to disable DNA transformation and to attenuate the virulence of S. pneumoniae. One of the mutated peptides, CSP1-E1A, inhibited development of competence in DNA transformation by outcompeting CSP1 in time and concn.-dependent manners. CSP1-E1A reduced the expression of pneumococcal virulence factors choline binding protein D (CbpD) and autolysin A (LytA) in vitro, and significantly reduced mouse mortality after lung infection. Furthermore, CSP1-E1A attenuated the acquisition of an antibiotic resistance gene and a capsule gene in vivo. Finally, the authors demonstrated that the strategy of using a peptide inhibitor is applicable to other CSP subtype, including CSP2. CSP1-E1A and CSP2-E1A were able to cross inhibit the induction of competence and DNA transformation in pneumococcal strains with incompatible ComD subtypes. These results demonstrate the applicability of generating competitive analogs of CSPs as drugs to control horizontal transfer of antibiotic resistance and virulence genes, and to attenuate virulence during infection by S. pneumoniae.
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251. 251
  Shaffer, C. L., Good, J. A. D., Kumar, S., Krishnan, K. S., Gaddy, J. A., Loh, J. T., Chappell, J., Almqvist, F., Cover, T. L., and Hadjifrangiskou, M. (2016) Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens. mBio 7, e00221-16 DOI: 10.1128/mBio.00221-16
  There is no corresponding record for this reference.
252. 252
  Grassi, L., Maisetta, G., Esin, S., and Batoni, G. (2017) Combination Strategies to Enhance the Efficacy of Antimicrobial Peptides against Bacterial Biofilms. Front. Microbiol. 8, 2409, DOI: 10.3389/fmicb.2017.02409
  252
  Combination Strategies to Enhance the Efficacy of Antimicrobial Peptides against Bacterial Biofilms
  Grassi Lucia; Maisetta Giuseppantonio; Esin Semih; Batoni Giovanna
  Frontiers in microbiology (2017), 8 (), 2409 ISSN:1664-302X.
  The great clinical significance of biofilm-associated infections and their inherent recalcitrance to antibiotic treatment urgently demand the development of novel antibiofilm strategies. In this regard, antimicrobial peptides (AMPs) are increasingly recognized as a promising template for the development of antibiofilm drugs. Indeed, owing to their main mechanism of action, which relies on the permeabilization of bacterial membranes, AMPs exhibit a strong antimicrobial activity also against multidrug-resistant bacteria and slow-growing or dormant biofilm-forming cells and are less prone to induce resistance compared to current antibiotics. Furthermore, the antimicrobial potency of AMPs can be highly increased by combining them with conventional (antibiotics) as well as unconventional bioactive molecules. Combination treatments appear particularly attractive in the case of biofilms since the heterogeneous nature of these microbial communities requires to target cells in different metabolic states (e.g., actively growing cells, dormant cells) and environmental conditions (e.g., acidic pH, lack of oxygen or nutrients). Therefore, the combination of different bioactive molecules acting against distinct biofilm components has the potential to facilitate biofilm control and/or eradication. The aim of this review is to highlight the most promising combination strategies developed so far to enhance the therapeutic potential of AMPs against bacterial biofilms. The rationale behind and beneficial outcomes of using AMPs in combination with conventional antibiotics, compounds capable of disaggregating the extracellular matrix, inhibitors of signaling pathways involved in biofilm formation (i.e., quorum sensing), and other peptide-based molecules will be presented and discussed.
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  Roy, R., Tiwari, M., Donelli, G., and Tiwari, V. (2018) Strategies for Combating Bacterial Biofilms: A Focus on Anti-Biofilm Agents and Their Mechanisms of Action. Virulence 9, 522– 554, DOI: 10.1080/21505594.2017.1313372
  253
  Strategies for combating bacterial biofilms: A focus on anti-biofilm agents and their mechanisms of action
  Roy, Ranita; Tiwari, Monalisa; Donelli, Gianfranco; Tiwari, Vishvanath
  Virulence (2018), 9 (1), 522-554CODEN: VIRUCS; ISSN:2150-5608. (Taylor & Francis, Inc.)
  A review. Biofilm refers to the complex, sessile communities of microbes found either attached to a surface or buried firmly in an extracellular matrix as aggregates. The biofilm matrix surrounding bacteria makes them tolerant to harsh conditions and resistant to antibacterial treatments. Moreover, the biofilms are responsible for causing a broad range of chronic diseases and due to the emergence of antibiotic resistance in bacteria it has really become difficult to treat them with efficacy. Furthermore, the antibiotics available till date are ineffective for treating these biofilm related infections due to their higher values of min. inhibitory concn. (MIC) and min. bactericidal concn. (MBC), which may result in in-vivo toxicity. Hence, it is critically important to design or screen anti-biofilm mols. that can effectively minimize and eradicate biofilm related infections. In the present article, we have highlighted the mechanism of biofilm formation with ref. to different models and various methods used for biofilm detection. A major focus has been put on various anti-biofilm mols. discovered or tested till date which may include herbal active compds., chelating agents, peptide antibiotics, lantibiotics and synthetic chem. compds. along with their structures, mechanism of action and their resp. MICs, MBCs, min. biofilm inhibitory concns. (MBICs) as well as the half maximal inhibitory concn. (IC50) values available in the literature so far. Different mode of action of anti biofilm mols. addressed here are inhibition via interference in the quorum sensing pathways, adhesion mechanism, disruption of extracellular DNA, protein, lipopolysaccharides, exopolysaccharides and secondary messengers involved in various signaling pathways. From this study, we conclude that the mols. considered here might be used to treat biofilm-assocd. infections after significant structural modifications, thereby investigating its effective delivery in the host. It should also be ensured that min. effective concn. of these mols. must be capable of eradicating biofilm infections with max. potency without posing any adverse side effects on the host.
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254. 254
  Chen, X., Zhang, L., Zhang, M., Liu, H., Lu, P., and Lin, K. (2018) Quorum Sensing Inhibitors: A Patent Review (2014–2018). Expert Opin. Ther. Pat. 28, 849– 865, DOI: 10.1080/13543776.2018.1541174
  254
  Quorum sensing inhibitors: a patent review (2014-2018)
  Chen, Xin; Zhang, Likun; Zhang, Mingxiang; Liu, Huayu; Lu, Panrui; Lin, Kejiang
  Expert Opinion on Therapeutic Patents (2018), 28 (12), 849-865CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
  A review. Quorum sensing (QS) is a cell d.-dependent phenomenon in which specific pathways are activated after autoinducers (AIs) outside the microorganism reach a threshold concn. QS creates a pos. feedback loop that induces a cascade of gene expression and causes biofilm formation, virulence and sporulation. QS signals are diverse, acyl-homoserine lactone (AHL), AI peptide (AIP) and AI-2 are three major categories of QS signals. QS inhibitors (QSIs) can disrupt or prevent the formation of biofilm and reduce virulence while exerting less selective pressure on the bacteria, suggesting that QSIs are potential alternatives for antibiotics. This review summarized the pertinent patents on QS inhibition available from 2014 to 2018. The authors analyze these patents and provided an overview of them and their potential applications. The main strategy for QS inhibition is to use the analogs of various QS signals to block downstream signal transducers. The inactivation of signal mols. or the stimulation of the immune response is also attractive strategies to inhibit QS. However, addnl. clin. trials are needed to assess their efficacy in mammals. In sum, QS inhibition can reduce the virulence of bacteria without affecting their growth or killing them and the reduced pressure may minimize the increasingly resistance.
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  Xiang, H., Cao, F., Ming, D., Zheng, Y., Dong, X., Zhong, X., Mu, D., Li, B., Zhong, L., Cao, J., Wang, L., Ma, H., Wang, T., and Wang, D. (2017) Aloe-Emodin Inhibits Staphylococcus Aureus Biofilms and Extracellular Protein Production at the Initial Adhesion Stage of Biofilm Development. Appl. Microbiol. Biotechnol. 101, 6671– 6681, DOI: 10.1007/s00253-017-8403-5
  255
  Aloe-emodin inhibits Staphylococcus aureus biofilms and extracellular protein production at the initial adhesion stage of biofilm development
  Xiang, Hua; Cao, Fengjiao; Ming, Di; Zheng, Yanyang; Dong, Xiaoyun; Zhong, Xiaobo; Mu, Dan; Li, Bangbang; Zhong, Ling; Cao, Junjie; Wang, Lin; Ma, Hongxia; Wang, Tiedong; Wang, Dacheng
  Applied Microbiology and Biotechnology (2017), 101 (17), 6671-6681CODEN: AMBIDG; ISSN:0175-7598. (Springer)
  Staphylococcus aureus (S. aureus) biofilms are clin. serious and play a crit. role in the persistence of chronic infections due to their ability to resist antibiotics. The inhibition of biofilm formation is viewed as a new strategy for the prevention of S. aureus infections. Here, we demonstrated that min. inhibitory concns. (MICs) of aloe-emodin exhibited no bactericidal activity against S. aureus but affected S. aureus biofilm development in a dose-dependent manner. Further studies indicated that aloe-emodin specifically inhibits the initial adhesion and proliferation stages of S. aureus biofilm development. SEM (SEM) indicated that the S. aureus ATCC29213 biofilm extracellular matrix is mainly composed of protein. Laser scanning confocal microscope assays revealed that aloe-emodin treatment primarily inhibited extracellular protein prodn. Moreover, the Congo red assay showed that aloe-emodin also reduced the accumulation of polysaccharide intercellular adhesin (PIA) on the cell surface. These findings will provide new insights into the mode of action of aloe-emodin in the treatment of infections by S. aureus biofilms.
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256. 256
  Wang, J., Nong, X.-H., Amin, M., and Qi, S.-H. (2018) Hygrocin C from Marine-Derived Streptomyces Sp. SCSGAA 0027 Inhibits Biofilm Formation in Bacillus Amyloliquefaciens SCSGAB0082 Isolated from South China Sea Gorgonian. Appl. Microbiol. Biotechnol. 102, 1417– 1427, DOI: 10.1007/s00253-017-8672-z
  256
  Hygrocin C from marine-derived Streptomyces sp. SCSGAA 0027 inhibits biofilm formation in Bacillus amyloliquefaciens SCSGAB0082 isolated from South China Sea gorgonian
  Wang, Jie; Nong, Xu-Hua; Amin, Muhammad; Qi, Shu-Hua
  Applied Microbiology and Biotechnology (2018), 102 (3), 1417-1427CODEN: AMBIDG; ISSN:0175-7598. (Springer)
  Several ansamycins have been reported to inhibit bacterial biofilm formation and accelerate the eradication of developed biofilms, but little is known about the effect of hygrocin C, an ansamycin, on bacterial biofilm formation. Here, hygrocin C was isolated from the marine-derived Streptomyces sp. SCSGAA 0027 and reported for the first time to be capable of inhibiting the biofilm formation of Staphylococcus aureus and Bacillus amyloliquefaciens SCSGAB0082 with the prodn. of anti-microbial lipopeptides from South China Sea gorgonian Subergorgia suberosa at concns. of less than min. inhibitory concns. Moreover, hygrocin C also promoted the eradication of developed biofilms, affected the biofilm architecture, and lowered the extracellular polymeric matrix formation, cell motility, and surface hydrophobicity in B. amyloliquefaciens, which was in accordance with the inhibition of biofilm formation. Furthermore, transcriptome anal. revealed that hygrocin C altered the transcripts of several genes assocd. with bacterial chemotaxis and flagellar, two-component system and the synthesis of arginine and histidine, which are important for bacterial biofilm formation. In conclusion, hygrocin C could be used as a potential biofilm inhibitor against S. aureus and B. amyloliquefaciens. But further genetic investigations are needed to provide more details for elucidation of the mol. mechanisms responsible for the effects of hygrocin C on B. amyloliquefaciens biofilm formation.
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257. 257
  Wunnoo, S., Saising, J., and Voravuthikunchai, S. P. (2017) Rhodomyrtone Inhibits Lipase Production, Biofilm Formation, and Disorganizes Established Biofilm in Propionibacterium Acnes. Anaerobe 43, 61– 68, DOI: 10.1016/j.anaerobe.2016.12.002
  257
  Rhodomyrtone inhibits lipase production, biofilm formation, and disorganizes established biofilm in Propionibacterium acnes
  Wunnoo, Suttiwan; Saising, Jongkon; Voravuthikunchai, Supayang Piyawan
  Anaerobe (2017), 43 (), 61-68CODEN: ANAEF8; ISSN:1075-9964. (Elsevier Ltd.)
  Virulence enzymes and biofilm a play crucial role in the pathogenesis of Propionibacterium acnes, a major causative agent of acne vulgaris. In the present study, the effects of rhodomyrtone, a pure compd. identified from Rhodomyrtus tomentosa (Aiton) Hassk. leaves ext. against enzyme prodn. and biofilm formation prodn. by 5 clin. isolates and a ref. strain were evaluated. The degree of hydrolysis by both lipase and protease enzymes significantly decreased upon treatment with the compd. at 0.125-0.25 μg/mL (p < 0.05). Lipolytic zones significantly reduced in all isolates while decrease in proteolytic activities was found only in 50% of the isolates. Rhodomyrtone at 1/16MIC and 1/8MIC caused significant redn. in biofilm formation of the clin. isolates (p < 0.05). Percentage viability of P. acnes within mature biofilm upon treated with the compd. at 4MIC and 8MIC ranged between 40% and 85%. Pronounced properties of rhodomyrtone suggest a path towards developing a novel anti-acne agent.
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258. 258
  Falagas, M. E. and Bliziotis, I. A. (2007) Pandrug-Resistant Gram-Negative Bacteria: The Dawn of the Post-Antibiotic Era?. Int. J. Antimicrob. Agents 29, 630– 636, DOI: 10.1016/j.ijantimicag.2006.12.012
  258
  Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era?
  Falagas, Matthew E.; Bliziotis, Ioannis A.
  International Journal of Antimicrobial Agents (2007), 29 (6), 630-636CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
  A review. The evolving problem of antimicrobial resistance in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae has led to the emergence of clin. isolates susceptible to only one class of antimicrobial agents and eventually to pandrug-resistant (PDR) isolates, i.e. resistant to all available antibiotics. The authors reviewed the available evidence from lab. and clin. studies that reported on polymyxin-resistant and/or PDR P. aeruginosa, A. baumannii or K. pneumoniae clin. isolates. Eleven lab. studies reported on isolates with resistance to polymyxins, three of which (including two surveillance studies) also included data regarding PDR isolates. In addn., two clin. studies (from Central and Southern Europe) reported on the clin. characteristics and outcomes of patients infected with PDR isolates. These data suggest that polymyxin-resistant or PDR P. aeruginosa, A. baumannii and K. pneumoniae clin. isolates are currently relatively rare. However, they have important global public health implications because of the therapeutic problems they pose. The fears for the dawn of a post-antibiotic era appear to be justified, at least for these three Gram-neg. bacteria. There must be an increase to preserve the activity of available antibiotics, or at least expand as much as possible the period of their use, while intense research efforts should be focused on the development and introduction into clin. practice of new antimicrobial agents.
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259. 259
  Asker, D., Awad, T. S., Baker, P., Howell, P. L., and Hatton, B. D. (2018) Non-Eluting, Surface-Bound Enzymes Disrupt Surface Attachment of Bacteria by Continuous Biofilm Polysaccharide Degradation. Biomaterials 167, 168– 176, DOI: 10.1016/j.biomaterials.2018.03.016
  259
  Non-eluting, surface-bound enzymes disrupt surface attachment of bacteria by continuous biofilm polysaccharide degradation
  Asker, Dalal; Awad, Tarek S.; Baker, Perrin; Howell, P. Lynne; Hatton, Benjamin D.
  Biomaterials (2018), 167 (), 168-176CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
  Bacterial colonization and biofilm formation on surfaces are typically mediated by the deposition of exopolysaccharides and conditioning protein layers. Pseudomonas aeruginosa is a nosocomial opportunistic pathogen that utilizes strain-specific exopolysaccharides such as Psl, Pel or alginate for both initial surface attachment and biofilm formation. To generate surfaces that resist P. aeruginosa colonization, we covalently bound a Psl-specific glycoside hydrolase (PslGh) to several, chem.-distinct surfaces using amine functionalization (APTMS) and glutaraldehyde (GDA) linking. In situ quartz crystal microbalance (QCM) expts. and fluorescence microscopy demonstrated a complete lack of Psl adsorption on the PslGh-bound surfaces. Covalently-bound PslGh was also found to significantly reduce P. aeruginosa surface attachment and biofilm formation over extended growth periods (8 days). The PslGh surfaces showed a ∼99.9% (∼3-log) redn. in surface assocd. bacteria compared to control (untreated) surfaces, or those treated with inactive enzyme. This work demonstrates a non-eluting 'bioactive' surface that specifically targets a mechanism of cell adhesion, and that surface-bound glycoside hydrolase can significantly reduce surface colonization of bacteria through local, continuous enzymic degrdn. of exopolysaccharide (Psl). These results have significant implications for the surface design of medical devices to keep bacteria in a planktonic state, and therefore susceptible to antibiotics and antimicrobials.
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260. 260
  Pritchard, M. F., Powell, L. C., Jack, A. A., Powell, K., Beck, K., Florance, H., Forton, J., Rye, P. D., Dessen, A., Hill, K. E., and Thomas, D. W. (2017) A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness. Antimicrob. Agents Chemother. 61, 61, DOI: 10.1128/AAC.00762-17
  There is no corresponding record for this reference.
261. 261
  de la Fuente-Nunez, C., Reffuveille, F., Haney, E. F., Straus, S. K., and Hancock, R. E. W. (2014) Broad-Spectrum Anti-Biofilm Peptide That Targets a Cellular Stress Response. PLoS Pathog. 10, e1004152 DOI: 10.1371/journal.ppat.1004152
  261
  Broad-spectrum anti-biofilm peptide that targets a cellular stress response
  de la Fuente-Nunez, Cesar; Reffuveille, Fany; Haney, Evan F.; Straus, Suzana K.; Hancock, Robert E. W.
  PLoS Pathogens (2014), 10 (5), e1004152/1-e1004152/12, 12 pp.CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  Bacteria form multicellular communities known as biofilms that cause two thirds of all infections and demonstrate a 10 to 1000 fold increase in adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that specifically target bacterial biofilms. Here we identified a potent anti-biofilm peptide 1018 that worked by blocking (p)ppGpp, an important signal in biofilm development. At concns. that did not affect planktonic growth, peptide treatment completely prevented biofilm formation and led to the eradication of mature biofilms in representative strains of both Gram-neg. and Gram-pos. bacterial pathogens including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Salmonella typhimurium and Burkholderia cenocepacia. Low levels of the peptide led to biofilm dispersal, while higher doses triggered biofilm cell death. We hypothesized that the peptide acted to inhibit a common stress response in target species, and that the stringent response, mediating (p)ppGpp synthesis through the enzymes RelA and SpoT, was targeted. Consistent with this, increasing (p)ppGpp synthesis by addn. of serine hydroxamate or over-expression of relA led to reduced susceptibility to the peptide. Furthermore, relA and spoT mutations blocking prodn. of (p)ppGpp replicated the effects of the peptide, leading to a redn. of biofilm formation in the four tested target species. Also, eliminating (p)ppGpp expression after two days of biofilm growth by removal of arabinose from a strain expressing relA behind an arabinose-inducible promoter, reciprocated the effect of peptide added at the same time, leading to loss of biofilm. NMR and chromatog. studies showed that the peptide acted on cells to cause degrdn. of (p)ppGpp within 30 min, and in vitro directly interacted with ppGpp. We thus propose that 1018 targets (p)ppGpp and marks it for degrdn. in cells. Targeting (p)ppGpp represents a new approach against biofilm-related drug resistance.
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262. 262
  Pletzer, D., Wolfmeier, H., Bains, M., and Hancock, R. E. W. (2017) Synthetic Peptides to Target Stringent Response-Controlled Virulence in a Pseudomonas Aeruginosa Murine Cutaneous Infection Model. Front. Microbiol. 8, 1867, DOI: 10.3389/fmicb.2017.01867
  262
  Synthetic Peptides to Target Stringent Response-Controlled Virulence in a Pseudomonas aeruginosa Murine Cutaneous Infection Model
  Pletzer Daniel; Wolfmeier Heidi; Bains Manjeet; Hancock Robert E W
  Frontiers in microbiology (2017), 8 (), 1867 ISSN:1664-302X.
  Microorganisms continuously monitor their surroundings and adaptively respond to environmental cues. One way to cope with various stress-related situations is through the activation of the stringent stress response pathway. In Pseudomonas aeruginosa this pathway is controlled and coordinated by the activity of the RelA and SpoT enzymes that metabolize the small nucleotide secondary messenger molecule (p)ppGpp. Intracellular ppGpp concentrations are crucial in mediating adaptive responses and virulence. Targeting this cellular stress response has recently been the focus of an alternative approach to fight antibiotic resistant bacteria. Here, we examined the role of the stringent response in the virulence of P. aeruginosa PAO1 and the Liverpool epidemic strain LESB58. A ΔrelA/ΔspoT double mutant showed decreased cytotoxicity toward human epithelial cells, exhibited reduced hemolytic activity, and caused down-regulation of the expression of the alkaline protease aprA gene in stringent response mutants grown on blood agar plates. Promoter fusions of relA or spoT to a bioluminescence reporter gene revealed that both genes were expressed during the formation of cutaneous abscesses in mice. Intriguingly, virulence was attenuated in vivo by the ΔrelA/ΔspoT double mutant, but not the relA mutant nor the ΔrelA/ΔspoT complemented with either gene. Treatment of a cutaneous P. aeruginosa PAO1 infection with anti-biofilm peptides increased animal welfare, decreased dermonecrotic lesion sizes, and reduced bacterial numbers recovered from abscesses, resembling the phenotype of the ΔrelA/ΔspoT infection. It was previously demonstrated by our lab that ppGpp could be targeted by synthetic peptides; here we demonstrated that spoT promoter activity was suppressed during cutaneous abscess formation by treatment with peptides DJK-5 and 1018, and that a peptide-treated relA complemented stringent response double mutant strain exhibited reduced peptide susceptibility. Overall these data strongly indicated that synthetic peptides target the P. aeruginosa stringent response in vivo and thus offer a promising novel therapeutic approach.
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263. 263
  Christensen, L. D., van Gennip, M., Jakobsen, T. H., Alhede, M., Hougen, H. P., Hoiby, N., Bjarnsholt, T., and Givskov, M. (2012) Synergistic Antibacterial Efficacy of Early Combination Treatment with Tobramycin and Quorum-Sensing Inhibitors against Pseudomonas Aeruginosa in an Intraperitoneal Foreign-Body Infection Mouse Model. J. Antimicrob. Chemother. 67, 1198– 1206, DOI: 10.1093/jac/dks002
  263
  Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model
  Christensen, Louise D.; van Gennip, Maria; Jakobsen, Tim H.; Alhede, Morten; Hougen, Hans Petter; Hoiby, Niels; Bjarnsholt, Thomas; Givskov, Michael
  Journal of Antimicrobial Chemotherapy (2012), 67 (5), 1198-1206CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  Quorum sensing (QS)-deficient Pseudomonas aeruginosa biofilms formed in vitro are more susceptible to tobramycin than QS-proficient P. aeruginosa biofilms, and combination treatment with a QS inhibitor (QSI) and tobramycin shows synergistic effects on the killing of in vitro biofilms. We extended these results to an in vivo P. aeruginosa foreign-body biofilm model. The effect of treatment initiated prophylactically was compared with treatment initiated 11 days post-insertion. Silicone tube implants pre-colonized with wild-type P. aeruginosa were inserted into the peritoneal cavity of BALB/c mice. Mice were treated with i.p. or s.c. injections of the QSIs furanone C-30, ajoene or horseradish juice ext. in combination with tobramycin. Mice were euthanized on day 1, 2, 3 or 14 post-infection for the estn. of quant. bacteriol., histopathol. and cytokine measurements. Combination treatment of P. aeruginosa resulted in a significantly lower cfu per implant as compared with the placebo groups for all QSIs tested. For early-initiated treatment, a significant difference in clearing was also obsd. between the combination group and the single-treatment groups, and between the placebo group and the single-treatment groups. In one case a significant difference in clearing was found between the two single-treatment groups. Synergistic antimicrobial efficacy could be achieved when treating mice with both a QSI and tobramycin, resulting in an increased clearance of P. aeruginosa in a foreign-body infection model. Our study highlights the important prospects in developing an early combinatory treatment strategy for chronic infections.
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264. 264
  Kissoyan, K. A. B., Bazzi, W., Hadi, U., and Matar, G. M. (2016) The Inhibition of Pseudomonas Aeruginosa Biofilm Formation by Micafungin and the Enhancement of Antimicrobial Agent Effectiveness in BALB/c Mice. Biofouling 32, 779– 786, DOI: 10.1080/08927014.2016.1199021
  264
  The inhibition of Pseudomonas aeruginosa biofilm formation by micafungin and the enhancement of antimicrobial agent effectiveness in BALB/c mice
  Kissoyan, Kohar Annie B.; Bazzi, Wael; Hadi, Usamah; Matar, Ghassan M.
  Biofouling (2016), 32 (7), 779-786CODEN: BFOUEC; ISSN:0892-7014. (Taylor & Francis Ltd.)
  Micafungin inhibits biofilm formation by impeding 1,3-β-D-glucan synthesis in Candida albicans. Since Pseudomonas aeruginosa also has 1,3-β-D-glucan in its cell wall, this study assessed the effects of antibacterial agents in vitro and in vivo on micafungin-treated biofilm-forming P. aeruginosa isolates. After treatment with micafungin as well as with a panel of four antibacterial agents, biofilm prodn. was significantly reduced as measured by spectrophotometry. The relative mRNA transcription levels for the genes encoding pellicles (pelC) and cell wall 1,3-β-D-glucan (ndvB), which were measured by quant. reverse transcription PCR (qRT-PCR), significantly decreased with micafungin treatment. In vivo, the survival rates of P. aeruginosa-infected BALB/c mice significantly increased after combined treatment with micafungin and each of the antibacterial agents. Of these treatments, the combination of micafungin with levofloxacin had the highest survival rate; this combination was the most effective treatment against P. aeruginosa-induced infection.
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265. 265
  Maiden, M. M., Hunt, A. M. A., Zachos, M. P., Gibson, J. A., Hurwitz, M. E., Mulks, M. H., and Waters, C. M. (2018) Triclosan Is an Aminoglycoside Adjuvant for Eradication of Pseudomonas Aeruginosa Biofilms. Antimicrob. Agents Chemother. 62, e00146-18 DOI: 10.1128/AAC.00146-18
  There is no corresponding record for this reference.
266. 266
  Worthington, R. J. and Melander, C. (2013) Combination Approaches to Combat Multidrug-Resistant Bacteria. Trends Biotechnol. 31, 177– 184, DOI: 10.1016/j.tibtech.2012.12.006
  266
  Combination approaches to combat multidrug-resistant bacteria
  Worthington, Roberta J.; Melander, Christian
  Trends in Biotechnology (2013), 31 (3), 177-184CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
  A review. The increasing prevalence of infections caused by multidrug-resistant bacteria is a global health problem that has been exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein, we describe recent developments toward combination therapies for the treatment of multidrug-resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems (TCSs). We also discuss screening of libraries of previously approved drugs to identify nonobvious antimicrobial adjuvants.
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267. 267
  Tyers, M. and Wright, G. D. (2019) Drug Combinations: A Strategy to Extend the Life of Antibiotics in the 21st Century. Nat. Rev. Microbiol. 17, 141– 155, DOI: 10.1038/s41579-018-0141-x
  267
  Drug combinations: a strategy to extend the life of antibiotics in the 21st century
  Tyers, Mike; Wright, Gerard D.
  Nature Reviews Microbiology (2019), 17 (3), 141-155CODEN: NRMACK; ISSN:1740-1526. (Nature Research)
  Antimicrobial resistance threatens a resurgence of life-threatening bacterial infections and the potential demise of many aspects of modern medicine. Despite intensive drug discovery efforts, no new classes of antibiotics have been developed into new medicines for decades, in large part owing to the stringent chem., biol. and pharmacol. requisites for effective antibiotic drugs. Combinations of antibiotics and of antibiotics with non-antibiotic activity-enhancing compds. offer a productive strategy to address the widespread emergence of antibiotic-resistant strains. In this Review, we outline a theor. and practical framework for the development of effective antibiotic combinations.
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268. 268
  Schmid, A., Wolfensberger, A., Nemeth, J., Schreiber, P. W., Sax, H., and Kuster, S. P. (2019) Monotherapy versus Combination Therapy for Multidrug-Resistant Gram-Negative Infections: Systematic Review and Meta-Analysis. Sci. Rep. 9, 15290, DOI: 10.1038/s41598-019-51711-x
  268
  Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis
  Schmid Adrian; Wolfensberger Aline; Nemeth Johannes; Schreiber Peter W; Sax Hugo; Kuster Stefan P
  Scientific reports (2019), 9 (1), 15290 ISSN:.
  Infections caused by carbapenemase-producing, multidrug-resistant (MDR), or extensively drug-resistant (XDR) Gram-negative bacteria constitute a major therapeutic challenge. Whether combination antibiotic therapy is superior to monotherapy remains unknown. In this systematic review and meta-analysis OVID MEDLINE, EMBASE, PubMed, The Cochrane Library, and Scopus databases were searched for randomized controlled trials (RCTs) and observational studies published by December 2016 comparing mono- with combination antibiotic therapy for infections with carbapenemase-producing, MDR, or XDR Gram-negative bacteria. Mortality and clinical cure rates served as primary and secondary outcome measures, respectively. Of 8847 initially identified studies, 53 studies - covering pneumonia (n = 10 studies), blood stream (n = 15), osteoarticular (n = 1), and mixed infections (n = 27) - were included. 41% (n = 1848) of patients underwent monotherapy, and 59% (n = 2666) combination therapy. In case series/cohort studies (n = 45) mortality was lower with combination- vs. monotherapy (RR 0.83, CI 0.73-0.93, p = 0.002, I(2) = 24%). Subgroup analysis revealed lower mortality with combination therapy with at least two in-vitro active antibiotics, in blood stream infections, and carbapenemase-producing Enterobacteriaceae. No mortality difference was seen in case-control studies (n = 6) and RCTs (n = 2). Cure rates did not differ regardless of study type. The two included RCTs had a high and unknown risk of bias, respectively. 16.7% (1/6) of case-control studies and 37.8% (17/45) of cases series/cohort studies were of good quality, whereas quality was poor in the remaining studies. In conclusion, combination antimicrobial therapy of multidrug-resistant Gram-negative bacteria appears to be superior to monotherapy with regard to mortality.
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269. 269
  Drusano, G. L., Hope, W., MacGowan, A., and Louie, A. (2016) Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1. Antimicrob. Agents Chemother. 60, 1194– 1201, DOI: 10.1128/AAC.02231-15
  269
  Suppression of emergence of resistance in pathogenic bacteria: keeping our powder dry, part 2
  Drusano, G. L.; Hope, William; MacGowan, Alasdair; Louie, Arnold
  Antimicrobial Agents and Chemotherapy (2016), 60 (3), 1194-1201CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
  We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done. The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence. A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clin. breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like Pseudomonas aeruginosa, Acinetobacter spp., and multidrug-resistant (MDR) Enterobacteriaceae. These lessons need to be applied to our old drugs as well to preserve them and to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chem. entities should have a resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects.
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270. 270
  Lee, J., Patel, G., Huprikar, S., Calfee, D. P., and Jenkins, S. G. (2009) Decreased Susceptibility to Polymyxin B during Treatment for Carbapenem-Resistant Klebsiella Pneumoniae Infection. J. Clin. Microbiol. 47, 1611– 2, DOI: 10.1128/JCM.02466-08
  270
  Decreased susceptibility to polymyxin B during treatment for carbapenem-resistant Klebsiella pneumoniae infection
  Lee Jooyun; Patel Gopi; Huprikar Shirish; Calfee David P; Jenkins Stephen G
  Journal of clinical microbiology (2009), 47 (5), 1611-2 ISSN:.
  There is no expanded citation for this reference.
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271. 271
  Goss, C. H. and Muhlebach, M. S. (2011) Review: Staphylococcus Aureus and MRSA in Cystic Fibrosis. J. Cystic Fibrosis 10, 298– 306, DOI: 10.1016/j.jcf.2011.06.002
  271
  Review: Staphylococcus aureus and MRSA in cystic fibrosis
  Goss, Christopher H.; Muhlebach, Marianne S.
  Journal of Cystic Fibrosis (2011), 10 (5), 298-306CODEN: JCFOAC; ISSN:1569-1993. (Elsevier B.V.)
  A review. Background: Staphylococcus aureus (S. aureus) is one of the earliest bacteria detected in infants and children with cystic fibrosis (CF). The rise of methicillin resistant S. aureus (MRSA) in the last 10 years has caused a lot of attention to this organism. Results: The aim of this review is to provide a general overview of methicillin sensitive S. aureus (MSSA) and MRSA, discuss special aspects of S. aureus in cystic fibrosis, and to review treatment concepts. Microbiol. of the organism will be reviewed along with data regarding the epidemiol. of both MSSA and MRSA. Antibiotic treatments both in regards to acute management and eradication of MSSA and MRSA will be reviewed. Prophylaxis of MSSA in CF remains controversial. Treatment with anti-staphylococcal agents reduces the infection rate with MSSA but may lead to a higher rate of infection with P. aeruginosa. In regards to MRSA, there is a paucity of clin. data regarding approaches to eradication. Conclusions: To advance the care of CF patients, controlled clin. trials are urgently needed to find the optimal approach to treating CF patients who are infected with either MSSA or MRSA.
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272. 272
  McCaughey, G., Diamond, P., Elborn, J. S., McKevitt, M., and Tunney, M. M. (2013) Resistance Development of Cystic Fibrosis Respiratory Pathogens When Exposed to Fosfomycin and Tobramycin Alone and in Combination under Aerobic and Anaerobic Conditions. PLoS One 8, e69763 DOI: 10.1371/journal.pone.0069763
  272
  Resistance development of cystic fibrosis respiratory pathogens when exposed to fosfomycin and tobramycin alone and in combination under aerobic and anaerobic conditions
  McCaughey, Gerard; Diamond, Paul; Elborn, J. Stuart; McKevitt, Matt; Tunney, Michael M.
  PLoS One (2013), 8 (7), e69763CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  Although antibiotics from different classes are frequently prescribed in combination to prevent the development of resistance amongst Cystic Fibrosis (CF) respiratory pathogens, there is a lack of data as to the efficacy of this approach. The authors have previously shown that a 4:1 (wt./wt.) combination of fosfomycin and tobramycin (F:T) has excellent activity against CF pathogens with increased activity under physiol. relevant anaerobic conditions. Therefore, the aim of this study was to det. whether F:T could delay or prevent the onset of resistance compared to either fosfomycin or tobramycin alone under aerobic and anaerobic conditions. The frequency of spontaneous mutants arising following exposure to fosfomycin, tobramycin and F:T was detd. for clin. Pseudomonas aeruginosa and MRSA isolates under aerobic and anaerobic conditions. The effect of sub-inhibitory concns. of fosfomycin, tobramycin and F:T on the induction of resistance was also investigated, with the stability of resistance and fitness cost assocd. with resistance assessed if it developed. P. aeruginosa and MRSA isolates had a lower frequency of spontaneous mutants to F:T compared to fosfomycin and tobramycin under both aerobic and anaerobic conditions. There was a max. two-fold increase in F:T MICs when P. aeruginosa and MRSA isolates were passaged in sub-inhibitory F:T for 12 days. In contrast, sequential resistance to fosfomycin and tobramycin developed quickly (n = 3 days for both) after passage in sub-inhibitory concns. Once developed, both fosfomycin and tobramycin resistance was stable and not assocd. with a biol. fitness cost to either P. aeruginosa or MRSA isolates. The results of this study suggest that F:T may prevent the development of resistance compared to fosfomycin or tobramycin alone under aerobic and physiol. relevant anaerobic conditions. F:T may be a potential treatment option in CF patients chronically colonized by MRSA and/or P. aeruginosa.
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273. 273
  Monedero, I. and Caminero, J. A. (2010) Management of Multidrug-Resistant Tuberculosis: An Update. Ther. Adv. Respir. Dis. 4, 117– 127, DOI: 10.1177/1753465810365884
  273
  Management of multidrug-resistant tuberculosis: an update
  Monedero Ignacio; Caminero Jose A
  Therapeutic advances in respiratory disease (2010), 4 (2), 117-27 ISSN:.
  Multidrug-resistant tuberculosis (MDR-TB) is threatening control of TB in many parts of the world. As a result of limited treatment options, patients have a poor prognosis and low chances of cure. This situation can be exacerbated by HIV epidemics. In some cases, the risk exists of a real shift from susceptible to resistant strains. Despite its relevance, currently there are more contradictions and confusion surrounding MDR-TB than hard evidence. No randomized controlled trials have been performed and published evidence is limited. Rather than just the selection of expensive drugs, MDR-TB management requires well-structured programmes with a comprehensive approach, which involve the actions of a wide range of participants. Even with current investments in research and development, new drugs and vaccines will take many years to be applied in low and middle income countries. The most successful results will depend on the optimization of existing tools. The majority of the patients, even those with extensive patterns of bacilli resistance, have a possibility of cure if current clinical knowledge and effective logistics are applied. This paper is a critical review of current best practice regarding the diagnosis and treatment of MDR-TB.
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274. 274
  REX Consortium (2013) Heterogeneity of Selection and the Evolution of Resistance. Trends Ecol. Evol. 28, 110– 118, DOI: 10.1016/j.tree.2012.09.001
  There is no corresponding record for this reference.
275. 275
  Takesue, Y., Nakajima, K., Ichiki, K., Ishihara, M., Wada, Y., Takahashi, Y., Tsuchida, T., and Ikeuchi, H. (2010) Impact of a Hospital-Wide Programme of Heterogeneous Antibiotic Use on the Development of Antibiotic-Resistant Gram-Negative Bacteria. J. Hosp. Infect. 75, 28– 32, DOI: 10.1016/j.jhin.2009.11.022
  275
  Impact of a hospital-wide programme of heterogeneous antibiotic use on the development of antibiotic-resistant Gram-negative bacteria
  Takesue Y; Nakajima K; Ichiki K; Ishihara M; Wada Y; Takahashi Y; Tsuchida T; Ikeuchi H
  The Journal of hospital infection (2010), 75 (1), 28-32 ISSN:.
  Although antibiotic heterogeneity has been proposed as a strategy to limit the emergence of antibiotic resistance, few clinical studies have been conducted to validate the concept. This paper evaluates a hospital-wide strategy of heterogeneous antibiotic use intended to reduce infections caused by resistant Gram-negative rods (GNR). A strategy termed 'periodic antimicrobial monitoring and supervision' (PAMS) was implemented between September 2006 and February 2008. The 18 month intervention period was compared with the preceding 18 months (12 months pre-establishment and 6 months preparation). During PAMS, recommended, restricted and off-supervised classes of antibiotics active against more resistant GNR were changed every 3 months according to the antimicrobial usage density and rates of resistance to those antibiotics in Pseudomonas aeruginosa during the preceding term. Usage of five categories of antibiotics was supervised by four full-time staff. Antibiotic heterogeneity was estimated using the Peterson index (AHI). AHI estimates were 0.66 and 0.74 during the observation period but rose after the introduction of PAMS (period 1: 0.84; period 2: 0.94; period 3: 0.88). The incidence of patients from whom resistant GNR were isolated decreased significantly (P<0.001), whereas isolation of multidrug-resistant (MDR) GNR decreased from 1.7% to 0.5% (P<0.001). There was no significant difference in the incidence of extended spectrum beta-lactamase-producing organisms. Rates of imipenem resistance among Pseudomonas aeruginosa improved during PAMS2. PAMS facilitated hospital-wide heterogeneous antibiotic usage which was associated with reduced rates of resistant GNR.
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276. 276
  Raymond, B. (2019) Five Rules for Resistance Management in the Antibiotic Apocalypse, a Road Map for Integrated Microbial Management. Evol. Appl. 12, 1079– 1091, DOI: 10.1111/eva.12808
  276
  Five rules for resistance management in the antibiotic apocalypse, a road map for integrated microbial management
  Raymond Ben
  Evolutionary applications (2019), 12 (6), 1079-1091 ISSN:1752-4571.
  Resistance to new antimicrobials can become widespread within 2-3 years. Resistance problems are particularly acute for bacteria that can experience selection as both harmless commensals and pathogenic hospital-acquired infections. New drugs, although welcome, cannot tackle the antimicrobial resistance crisis alone: new drugs must be partnered with more sustainable patterns of use. However, the broader experience of resistance management in other disciplines, and the assumptions on which resistance rests, is not widely appreciated in clinical and microbiological disciplines. Improved awareness of the field of resistance management could improve clinical outcomes and help shape novel solutions. Here, the aim is to develop a pragmatic approach to developing a sustainable integrated means of using antimicrobials, based on an interdisciplinary synthesis of best practice, recent theory and recent clinical data. This synthesis emphasizes the importance of pre-emptive action and the value of reducing the supply of genetic novelty to bacteria under selection. The weight of resistance management experience also cautions against strategies that over-rely on the fitness costs of resistance or low doses. The potential (and pitfalls) of shorter courses, antibiotic combinations and antibiotic mixing or cycling are discussed in depth. Importantly, some of variability in the success of clinical trials of mixing approaches can be explained by the number and diversity of drugs in a trial, as well as whether trials encompass single wards or the wider transmission network that is a hospital. Consideration of the importance of data, and of the initially low frequency of resistance, leads to a number of additional recommendations. Overall, reduction in selection pressure, interference with the transmission of problematic genotypes and multidrug approaches (combinations, mixing or cycling) are all likely to be required for sustainability and the protection of forthcoming drugs.
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277. 277
  Paul, M., Lador, A., Grozinsky-Glasberg, S., and Leibovici, L. (2014) Beta Lactam Antibiotic Monotherapy versus Beta Lactam-Aminoglycoside Antibiotic Combination Therapy for Sepsis. Cochrane database Syst. Rev. (1), CD003344, DOI: 10.1002/14651858.CD003344.pub3
  There is no corresponding record for this reference.
278. 278
  Tamma, P. D., Cosgrove, S. E., and Maragakis, L. L. (2012) Combination Therapy for Treatment of Infections with Gram-Negative Bacteria. Clin. Microbiol. Rev. 25, 450– 470, DOI: 10.1128/CMR.05041-11
  278
  Combination therapy for treatment of infections with Gram-negative bacteria
  Tamma, Pranita D.; Cosgrove, Sara E.; Maragakis, Lisa L.
  Clinical Microbiology Reviews (2012), 25 (3), 450-470CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
  The findings for this review as well as from several meta-analyses do not support the use of combination antimicrobial therapy for definitive treatment of infections with Gram-neg. bacteria. It should be noted that combination therapy may have some value in a specific subset of patients with severe sepsis, and well-controlled randomized studies are necessary to answer this question. Many of the early studies that supported the concept of combination therapy used aminoglycoside monotherapy as the comparator group, a clin. strategy that has been subsequently shown to be inferior. With the advent of broad-spectrum antipseudomonal β-lactam agents, studies have not shown an advantage to adding a second agent. There are three potential advantages to combination antimicrobial therapy for infections with Gram-neg. bacteria that are generally cited: (i) an increased likelihood that the infective pathogen will be susceptible to at least one of the components of an empiric combination regimen, (ii) the synergistic effect afforded by the use of two agents, and (iii) protection against emergence of resistance with combination therapy. With regard to the first point, the use of empiric combination therapy for critically ill patients is certainly appropriate to broaden the spectrum of activity and to increase the likelihood that the regimen contains a single agent that is active against the pathogen, but there is insufficient evidence showing a benefit of a second agent for continued therapy once pathogens and antimicrobial susceptibilities are known. Although synergy may have a role when treating a highly resistant organism with MICs in the intermediate to resistant range, assuming that the pathogen is susceptible to one antibiotic, there does not appear to be a "synergistic" benefit that translates to an incremental clin. benefit with the addn. of a second agent. Finally, clin. studies of infections with Gram-neg. bacteria have shown no difference in the emergence of resistance during antimicrobial therapy with combination therapy vs. monotherapy. Ensuring that the dose, frequency of administration, and duration over which an antibiotic is infused are optimized is likely more important in the prevention of resistance than the addn. of a second agent. As the flow of new antibacterial drugs into the market has slowed coupled with the increasing prevalence of MDRGN infections, saving the second agent for when actually necessary is vital in the war against antimicrobial resistance.
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279. 279
  Lipsitch, M. and Levin, B. R. (1997) The Population Dynamics of Antimicrobial Chemotherapy. Antimicrob. Agents Chemother. 41, 363– 373, DOI: 10.1128/AAC.41.2.363
  279
  The population dynamics of antimicrobial chemotherapy
  Lipsitch, Marc; Levin, Bruce R.
  Antimicrobial Agents and Chemotherapy (1997), 41 (2), 363-373CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The authors present and analyze a series of math. models for the emergence of resistance during antibiotic treatment of an infected host. The models consider the population dynamics of antibiotic-sensitive and -resistant bacteria during the course of treatment and addresses the following problems: (i) the probability of obtaining a resistant mutant during the course of treatment as a function of antibiotic exposure; (ii) the conditions under which high, infrequent doses of an antibiotic are predicted to succeed in preventing the emergence of resistance; (iii) the conditions for the success of multiple drug treatment in suppressing the emergency of resistance and the relation between antibiotic synergism and suppression of resistance; and (i.v.) the conditions under which non-adherence to the prescribed treatment regimen is predicted to result in treatment failure due to resistance. The authors analyze the predictions of the model for interpreting and extrapolating existing exptl. studies of treatment efficacy and for optimizing treatment protocols to prevent the emergence of resistance.
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280. 280
  Raymond, B., Wright, D. J., Crickmore, N., and Bonsall, M. B. (2013) The Impact of Strain Diversity and Mixed Infections on the Evolution of Resistance to Bacillus Thuringiensis. Proc. R. Soc. London, Ser. B 280, 20131497, DOI: 10.1098/rspb.2013.1497
  There is no corresponding record for this reference.
281. 281
  Pena-Miller, R., Laehnemann, D., Jansen, G., Fuentes-Hernandez, A., Rosenstiel, P., Schulenburg, H., and Beardmore, R. (2013) When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load: The Smile-Frown Transition. PLoS Biol. 11, e1001540 DOI: 10.1371/journal.pbio.1001540
  281
  When the most potent combination of antibiotics selects for the greatest bacterial load: the smile-frown transition
  Pena-Miller, Rafael; Laehnemann, David; Jansen, Gunther; Fuentes-Hernandez, Ayari; Rosenstiel, Philip; Schulenburg, Hinrich; Beardmore, Robert
  PLoS Biology (2013), 11 (4), e1001540CODEN: PBLIBG; ISSN:1545-7885. (Public Library of Science)
  Conventional wisdom holds that the best way to treat infection with antibiotics is to 'hit early and hit hard'. A favored strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal. We combine math. modeling, evolution expts., whole genome sequencing and genetic manipulation of a resistance mechanism to demonstrate that deploying synergistic antibiotics can, in practice, be the worst strategy if bacterial clearance is not achieved after the first treatment phase. As treatment proceeds, it is only to be expected that the strength of antibiotic synergy will diminish as the frequency of drug-resistant bacteria increases. Indeed, antibiotic efficacy decays exponentially in our five-day evolution expts. However, as the theory of competitive release predicts, drug-resistant bacteria replicate fastest when their drug-susceptible competitors are eliminated by overly-aggressive treatment. Here, synergy exerts such strong selection for resistance that an antagonism consistently emerges by day 1 and the initially most aggressive treatment produces the greatest bacterial load, a fortiori greater than if just one drug were given. Whole genome sequencing reveals that such rapid evolution is the result of the amplification of a genomic region contg. four drug-resistance mechanisms, including the acrAB efflux operon. When this operon is deleted in genetically manipulated mutants and the evolution expt. repeated, antagonism fails to emerge in five days and antibiotic synergy is maintained for longer. We therefore conclude that unless super-inhibitory doses are achieved and maintained until the pathogen is successfully cleared, synergistic antibiotics can have the opposite effect to that intended by helping to increase pathogen load where, and when, the drugs are found at sub-inhibitory concns.
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282. 282
  MacLean, R. C., Hall, A. R., Perron, G. G., and Buckling, A. (2010) The Population Genetics of Antibiotic Resistance: Integrating Molecular Mechanisms and Treatment Contexts. Nat. Rev. Genet. 11, 405– 414, DOI: 10.1038/nrg2778
  282
  The population genetics of antibiotic resistance: Integrating molecular mechanisms and treatment contexts
  MacLean, R. Craig; Hall, Alex R.; Perron, Gabriel G.; Buckling, Angus
  Nature Reviews Genetics (2010), 11 (6), 405-414CODEN: NRGAAM; ISSN:1471-0056. (Nature Publishing Group)
  A review. The authors discuss the evolutionary dynamics of antibiotic resistance in bacteria in relation to the complex interplay between population genetic factors and the spatial and temporal pattern of antibiotic use. Despite efforts from a range of disciplines, our ability to predict and combat the evolution of antibiotic resistance in pathogenic bacteria is limited. This is because resistance evolution involves a complex interplay between the specific drug, bacterial genetics and both natural and treatment ecol. Incorporating details of the mol. mechanisms of drug resistance and ecol. into evolutionary models has proved useful in predicting the dynamics of resistance evolution. However, putting these models to practical use will require extensive collaboration between mathematicians, mol. biologists, evolutionary ecologists and clinicians.
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283. 283
  Hegreness, M., Shoresh, N., Damian, D., Hartl, D., and Kishony, R. (2008) Accelerated Evolution of Resistance in Multidrug Environments. Proc. Natl. Acad. Sci. U. S. A. 105, 13977– 13981, DOI: 10.1073/pnas.0805965105
  283
  Accelerated evolution of resistance in multidrug environments
  Hegreness, Matthew; Shoresh, Noam; Damian, Doris; Hartl, Daniel; Kishony, Roy
  Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (37), 13977-13981CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The emergence of resistance during multidrug chemotherapy impedes the treatment of many human diseases, including malaria, TB, HIV, and cancer. Although certain combination therapies have long been known to be more effective in curing patients than single drugs, the impact of such treatments on the evolution of drug resistance is unclear. In particular, very little is known about how the evolution of resistance is affected by the nature of the interactions-synergy or antagonism-between drugs. Here we directly measure the effect of various inhibitory and subinhibitory drug combinations on the rate of adaptation. We develop an automated assay for monitoring the parallel evolution of hundreds of Escherichia coli populations in a two-dimensional grid of drug gradients over many generations. We find a correlation between synergy and the rate of adaptation, whereby evolution in more synergistic drug combinations, typically preferred in clin. settings, is faster than evolution in antagonistic combinations. We also find that resistance to some synergistic combinations evolves faster than resistance to individual drugs. The accelerated evolution may be due to a larger selective advantage for resistance mutations in synergistic treatments. We describe a simple geometric model in which mutations conferring resistance to one drug of a synergistic pair prevent not only the inhibitory effect of that drug but also its enhancing effect on the other drug. Future study of the profound impact that synergy and other drug-pair properties can have on the rate of adaptation may suggest new treatment strategies for combating the spread of antibiotic resistance.
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284. 284
  Liu, J., Gefen, O., Ronin, I., Bar-Meir, M., and Balaban, N. Q. (2020) Effect of Tolerance on the Evolution of Antibiotic Resistance under Drug Combinations. Science 367, 200– 204, DOI: 10.1126/science.aay3041
  284
  Effect of tolerance on the evolution of antibiotic resistance under drug combinations
  Liu, Jiafeng; Gefen, Orit; Ronin, Irine; Bar-Meir, Maskit; Balaban, Nathalie Q.
  Science (Washington, DC, United States) (2020), 367 (6474), 200-204CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  Drug combinations are widely used in clin. practice to prevent the evolution of resistance. However, little is known about the effect of tolerance, a different mode of survival, on the efficacy of drug combinations for preventing the evolution of resistance. In this work, we monitored Staphylococcus aureus strains evolving in patients under treatment. We detected the rapid emergence of tolerance mutations, followed by the emergence of resistance, despite the combination treatment. Evolution expts. on the clin. strains in vitro revealed a new way by which tolerance promotes the evolution of resistance under combination treatments. Further expts. under different antibiotic classes reveal the generality of the effect. We conclude that tolerance is an important factor to consider in designing combination treatments that prevent the evolution of resistance.
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Multitarget Approaches against Multiresistant SuperbugsClick to copy article linkArticle link copied!

ACS Infectious Diseases

Abstract

SPECIAL ISSUE

Part 1: Multitarget Compounds

Intrinsically Multi-effective

Figure 1

Multiple Targets in the Same Pathway

Multiple Targets in Different Pathways

Designer Dual-Target Compounds

Multifunctional Compounds

Part 2: Antibiotic Combinations

Figure 2

Antibiotic Synergy

Figure 3

Permeabilizers

Figure 4

Sensitizers

Resistance Breakers

Prevention of Horizontal Gene Transfer

Biofilm Inhibitors

Multidrug Approaches

Challenges of Combination Therapy

Conclusion

Author Information

Acknowledgments

References

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Abstract

Figure 1

Figure 2

Figure 3

Figure 4

References

Multitarget Approaches against Multiresistant Superbugs
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