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Conjugates of Aminoglycosides with Stapled Peptides as a Way to Target Antibiotic-Resistant Bacteria

Cite this: ACS Omega 2023, 8, 21, 19047–19056
Publication Date (Web):May 16, 2023
https://doi.org/10.1021/acsomega.3c02071

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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The misuse and overuse of antibiotics led to the development of bacterial resistance to existing aminoglycoside (AMG) antibiotics and limited their use. Consequently, there is a growing need to develop effective antimicrobials against multidrug-resistant bacteria. To target resistant strains, we propose to combine 2-deoxystreptamine AMGs, neomycin (NEO) and amikacin (AMK), with a membrane-active antimicrobial peptide anoplin and its hydrocarbon stapled derivative. The AMG–peptide hybrids were conjugated using the click chemistry reaction in solution to obtain a non-cleavable triazole linker and by disulfide bridge formation on the resin to obtain a linker cleavable in the bacterial cytoplasm. Homo-dimers connected via disulfide bridges between the N-terminus thiol analogues of anoplin and hydrocarbon stapled anoplin were also synthesized. These hybrid compounds show a notable increase in antibacterial and bactericidal activity, as compared to the unconjugated ones or their combinations, against Gram-positive and Gram-negative bacteria, especially for the strains resistant to AMK or NEO. The conjugates and disulfide peptide dimers exhibit low hemolytic activity on sheep red blood erythrocytes.

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Introduction

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Tackling antibiotic resistance has become one of the world’s biggest challenges. (1) Already 700,000 people die each year from drug-resistant bacterial infections. It is estimated that the death toll could rise to 10 million by 2050, which is more than today’s cancer death rate. (2) In addition, because of the misuse of antibiotics during the COVID-19 epidemic, the problem exacerbated. (3,4) Overuse of antibiotics to prevent or treat bacterial complications in infected patients has rapidly increased antibiotic resistance. Therefore, the development of new effective antimicrobial agents, especially against multidrug-resistant (MDR) strains, is essential.
Aminoglycosides (AMGs) are one of the first discovered broad-spectrum antibiotics active against Gram-positive and Gram-negative bacteria. (5,6) Since World War II, they have been used in antibacterial therapy and medicinal chemistry. (7,8) These positively charged, modified polysaccharides enter cells through pore channels via an energy-dependent mechanism. (9) AMGs primarily target bacterial ribosomes and block protein translation, resulting in the inhibition of bacterial growth. (10−13)
However, bacteria developed several resistance mechanisms drastically reducing the effectiveness of AMG. (7,14,15) These include enzymatic modifications of AMG by bacterial enzymes, active transport outside the bacterial cell by the efflux pumps, and mutations and methylations of ribosomal RNA. (7,16) In efforts to overcome the resistance problem, AMGs have been chemically modified to increase their ribosomal RNA binding affinity, antibacterial activity and selectivity, and reduce their susceptibility to AMG-modifying enzymes. (16−20) Apparently, AMG syntheses and modifications pose a challenge due to their structural complexity and rich stereochemistry. (10)
Nevertheless, the modification of neomycin (NEO) in the C5′ position of ring III (Figure 1) by different functional groups has served as a viable strategy to address the resistance problem. (21−23) These NEO modifications directed the development of new AMG. (24−26) In addition, the primary hydroxyl group in the C6′ position of amikacin (AMK) was found suitable for the incorporation of hydrogen bond donors or acceptors and other functional groups (Figure 1). (27) For example, AMK modifications by methylamine inserted in the C6′ position via the triazole ring showed a two-fold increase in activity against a resistant hospital-associated MRSA strain of Staphylococcus aureus ATCC 33591.

Figure 1

Figure 1. Chemical structures of the elements forming the conjugates: aminoglycosides [amikacin (AMK) and neomycin (NEO)], amphipathic peptides (anoplin and anoplin[2-6]), and the linker type (triazole and disulfide bond). The helical wheel projection (predicted by Heliquest (60)) of the peptides and the positions at which the elements are connected are also shown (red and blue waves).

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An important class of antibacterials are antimicrobial peptides (AMPs). (28−32) Many AMPs, which adopt a helical conformation upon interaction with the bacterial membranes, have been discovered. (33) The amphipathic nature of AMP allows them to selectively interact with the negatively charged bacterial cell surface and hydrophobic fatty acids. (29,33) A common AMP antibacterial mechanism is associated with their ability to adopt an active secondary structure that permeabilizes and destabilizes the membrane. (34) However, natural AMPs have many limitations, such as weak stability in the enzymatic environment and cytotoxicity. (34) Therefore, many AMP modifications have been introduced to enhance their antibacterial activity and biostability and to decrease toxicity to eukaryotic cells. (35,36)
One of the methods used to modify peptides by initiating or stabilizing a helical structure is peptide stapling. (37) The idea is based on replacing two amino acids located on the hydrophobic side of an amphipathic peptide with unnatural ones. These unnatural amino acids are inserted into the sequence between one turn of the helix or, in a longer peptide, two helical turns. Furthermore, a covalent bridge is formed between the side chains of the inserted amino acids. (37) Therefore, hydrocarbon stapling can impart structural rigidity to the peptide and reinforce or improve the stability of the secondary structure (typically a helical conformation). This technique has become useful particularly for AMP. (38,39) Several reports have shown that stapled antimicrobial peptides (StAMPs) adopt a stable helix, are resistant to proteases, destabilize bacterial membranes, and have better antibacterial activity. (40−43) The therapeutic potential of such StAMP in vivo was also demonstrated. (42)
We focus on the anoplin peptide whose modifications and antibacterial potential have been recently studied. (44−50) Anoplin is a naturally found amphipathic peptide (Nter-Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-Cter) derived from the venom sac of the solitary wasp, with rather low antibacterial activity. However, we and others demonstrated the antibacterial potential of anoplin derivatives. (49,51) Typically, amphipathic and stable secondary structures are key for cytoplasmic membrane disruption and effective antibacterial activity of peptides. (28) We showed that anoplin adopts a helical structure in the presence of membrane mimics and lipopolysaccharides. (48) We also showed that hydrocarbon stapling of anoplin stabilizes its helical structure and increases its proteolytic stability and antibacterial activity (up to 8–16 fold as compared to unmodified anoplin). (49) In addition, anoplin stapled between the second and sixth amino acid is neither hemolytic nor cytotoxic. (49)
Several strategies to develop new antimicrobial agents were based on conjugation of two compounds in order to increase their uptake and activity. (52) Also, peptide motifs conjugated with antibiotics destabilize bacterial membranes, thereby improving the activity of the components. (53) Many studies showed that coupling of AMG with amino acids, peptides, peptide nucleic acids, and lipids increased their antimicrobial activity. (18,54,55) A recent example involves Pentobra, a peptide conjugated with tobramycin, which was found to destabilize the bacterial cell membrane better than tobramycin alone, suggesting that the Pentobra conjugate is more selective against the membrane of Escherichia coli. (53) Another conjugate of NEO with hydrophobic polycarbamates showed a remarkable 256-fold antibacterial activity enhancement against S. aureus MRSA ATCC 33592 as compared to unmodified NEO. (56)
Therefore, we hypothesized that conjugating AMG with AMP would enhance the antibacterial activity of AMG, especially against the AMG-resistant strains. We selected NEO and AMK, from the class of 2-deoxystreptamine AMG, and the amphipathic and α-helical anoplin analogues. To determine the effect of the linker, we conjugated the segments through a non-cleavable triazole ring or a cleavable disulfide bond that is cleaved in the presence of a reducing agent, glutathione, found in the bacterial cytoplasm. (57) For conjugation, we used either the copper-catalyzed alkyne–azide cycloaddition (CuAAC), a click chemistry technique broadly used in bioconjugation of molecules or disulfide bridge formation. (58,59)
In this work, we compare different strategies applied to improve the antibacterial activity including conjugation of AMG antibiotics with AMP, peptide stapling, and the combination of both. We tested the antibacterial and bactericidal activity of the conjugates against different Gram-negative E. coli and Gram-positive S. aureus strains, including the antibiotic-resistant ones. We also examined the hemolytic activity of the hybrids on sheep red blood cells (RBCs). To the best of our knowledge, this is the first work involving anoplin and its stapled analogue as components of conjugates with antibiotics.

Results and Discussion

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Design and Synthesis of the AMG and Peptide Conjugates

We proposed two approaches to conjugate AMG and peptides (Figure 1). One was based on the alkyne derivatives of peptides and azide derivatives of AMG and their conjugation using the click chemistry reaction. The other was based on the thiol peptide derivatives and pyridine disulfide NEO and their conjugation via disulfide bond formation. These different conjugation strategies gave either a non-cleavable or cleavable linker between the AMG and peptides. Thus, we could determine whether the stability of the linker in the intracellular environment impacts the antimicrobial activity of these conjugates.
We used AMK as a representative of the 4,6-disubstituted-2-deoxystreptamines and neomycin B as a representative of the 4,5-disubstituted-2-deoxystreptamines (Figure 1). Both have been investigated for structural modifications. (24,26,27,61) Neomycin B was selected because of its low price and low biological activity toward several MDR bacteria including the S. aureus ATCC BAA1720 MRSA strain. (24) AMK was chosen because of high resistance of the E. coli WR 3551/98 strain to this antibiotic and its commercial availability. (61) The primary hydroxyl group in these AMGs (C5′ in neomycin B and C6′ in AMK, Figure 1) is preferred for modifications due to its high reactivity and ease of introducing other functional groups. (24,26,27) Derivatives of AMK and neomycin B were obtained by introducing two different active groups: azide and thiopyridine. The azide derivatives of neomycin B [NEO(Boc)6-N3] and AMK [AMK(Boc)4-N3] were synthesized according to the adapted protocols. (27,62,63) Briefly, all AMG amine groups were protected by a tert-butyloxycarbonyl (Boc) group, and then, in a substitution reaction of the triisopropylbenzenesulfonyl group with an azide group, the derivatives were prepared. NEO-pyridyl [NEO(Boc)6-SSPyr] was prepared by replacing the triisopropylbenzenesulfonyl group in a two-step reaction to introduce the active thiopyridine group (Scheme 1, details are given in Materials and Methods, Figures S1–S3).

Scheme 1

Scheme 1. Two-Step Synthesis of the Protected NEO-Pyridyl Disulfidea
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aReagents and conditions: (a) thiourea, EtOH, reflux, 3 days and (b) 2-mercaptopyridine, MeNH2, MeOH, rt, 18 h. OTPS–─2,4,6 triisopropylbenzenesulfonate.

As a peptide for conjugation, we selected anoplin and its hydrocarbon stapled form; both are amidated at the C-terminus for biostability and bear the same net charge of +4e (Figures 1, S4 and S5). We modified the N-terminus of anoplin and anoplin[2-6] by coupling the 10-undecynoic acid and cysteine with the methoxytrityl (Mmt) protecting group. The Mmt group was chosen because of its simple deprotection conditions and orthogonal character with respect to other protecting groups in the peptide sequence. (64) Appropriately, to conjugate with AMG, alkyne-anoplin and alkyne-anoplin[2-6] were used for the click reaction, while peptides with the additional Cys in the sequence were used to obtain hybrids linked via a disulfide bond (Figures 1, S6 and S7). As a result of the reaction of NEO(Boc)6-N3 or AMK(Boc)4-N3 with alkyne-anoplin or alkyne-anoplin[2-6], the 1,2,3-triazole ring was formed (Scheme S1, Table S1, Figures S8–S11). (65) The triazole ring is not susceptible to hydrolysis, reduction, and oxidation, so it is not cleaved in the bacterial cell, contrary to the disulfide bond.
The second conjugation strategy uses the redox-sensitive formation of disulfide bonds. To avoid the limitations in disulfide bond formation, including side reactions and lower yield due to the appearance of dimeric products, we used the method of forming the disulfide bond on the resin. (58,66,67) Accordingly, the resins with attached Cys(Mmt)-anoplin or Cys(Mmt)-anoplin[2-6] were treated with a low concentration of trifluoroacetic acid (TFA) solution to remove the Mmt group and finally to obtain the free thiol group at the N-terminus of anoplin and anoplin[2-6]. (68) The NEO-SS-anoplin and NEO-SS-anoplin[2-6] (Scheme S2, Table S1, Figures S12 and S13) were obtained by nucleophilic substitution between the thiol group and active thiopyridine group. (69)
Since there is evidence that peptide dimers can structurally stabilize the natural or engineered peptides and often improve their biological activity, (70) we also obtained the peptide homo-dimers by the formation of disulfide bonds through the free thiol group at the peptide’s N-terminus (Figures 1, S14, and S15). A disulfide bond was spontaneously formed during the reaction in the aqueous solution.

Antibacterial Activity

The antibacterial activity of the conjugates was assessed by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Gram-negative E. coli (K12 MG 1655 and WR 3551/98) and Gram-positive S. aureus (ATCC 29213 and ATCC BAA1720 MRSA) strains (Table 1, Figures S16–S23).
Table 1. MIC and MBC of the Conjugates and Their Monomeric Forms on Representative E. coli and S. aureus Bacterial Strains
 MIC/MBC [μM]
 E. coli K12 MG1655E. coli WR 3551/98S. aureus ATCC 29213S. aureus ATCC BAA1720 MRSA
conjugatesMICMBCMICMBCMICMBCMICMBC
NEO-anoplin88–1616161616–323232
NEO-anoplin[2-6]8816168161616
AMK-anoplin16161616–3232>32>32>32
AMK-anoplin[2-6]4816161616–3232≥32
NEO-SS-anoplin8881648>32>32
NEO-SS-anoplin[2-6]88–16816483232
amikacin (AMK)48–16>32>328832≥32
neomycin (NEO)444812>32>32
anoplin-SS-anoplin481216321632
anoplin[2-6]-SS-anoplin[2-6]444416161616–32
anoplin32≥32>32>32>32>32>32>32
anoplin[2-6]4844–81616–321632
NEO + anoplina4       
NEO + anoplin[2-6]a4   2   
AMK + anoplina4       
AMK + anoplin[2-6]a4   8   
a

MIC values for 1:1 molar mixtures of compounds were derived from checkerboard experiments. For some instances, MIC determination was not possible due to its values exceeding the tested range for at least one of the tested compounds from the mix.

For AMK-anoplin and AMK-anoplin[2-6], we observed at least two-fold MIC decrease (16 μM) on the AMK-resistant E. coli WR 3551/98 as compared to AMK alone (MIC > 32 μM). In turn, NEO-anoplin[2-6] and NEO-anoplin inhibited the growth of NEO-resistant S. aureus MRSA at concentrations of 16 and 32 μM, respectively. Thus, attachment of unmodified anoplin to AMG makes the antibiotic active against AMG-resistant strains even though anoplin alone is not active against these strains.
Overall, anoplin alone did not inhibit the growth of the selected strains in the tested concentration range up to 32 μM. However, conjugating anoplin to AMK or NEO, in many instances, resulted in a measurable MIC in contrast to free anoplin.
Conjugation of the stapled anoplin[2-6] to AMK or NEO (as in NEO-anoplin[2-6] and AMK-anoplin[2-6]) showed similar or slightly better antibacterial activity, especially against S. aureus 29213 and E. coli K12, as compared to the conjugates with unstapled anoplin. Anoplin[2-6] proved a helical peptide that effectively penetrated the membrane and cell wall mimics of the E. coli K12 strain and showed 4–16 μM MIC against Gram-negative strains. (49) Therefore, we suppose that the better activity of AMG-anoplin[2-6] conjugates is related to stronger affinity of the stapled peptide to the bacterial cell membrane. Anoplin[2-6] as a permeabilizing agent affects bacterial cell membrane integrity. (49) We suspect that this disruption of integrity of bacterial membranes by introducing the staple may also facilitate the transport of AMG into the bacteria.
The disulfide bond is often used as a linker between the conjugated segments in hybrid compounds. (57) Furthermore, the degradability of such linkers in the intra-bacterial environment is used to promote the drug to reach its target. (58,59,71) Interestingly, NEO conjugates with peptides linked through disulfide bonds (NEO-SS-anoplin and NEO-SS-anoplin[2-6]) inhibited bacterial growth at lower concentrations than the corresponding conjugates with a non-cleavable linker. For the E. coli WR 3551/98 strain, it was a two-fold increase in activity. In general, we obtained better antibacterial activities for the conjugates linked through a disulfide bond compared to the same conjugates linked through a non-cleavable triazole ring.
The peptide dimers also showed similar or higher antibacterial activity compared to their monomeric forms. Interestingly, we found a remarkable 32-fold MIC enhancement against E. coli WR 3551/98 for the anoplin-SS-anoplin dimer (compared to anoplin monomer), while dimerization of stapled anoplin[2-6] via a disulfide bond showed a similar effect as anoplin[2-6] alone.
In contrast to anoplin[2-6], the dimeric form of anoplin greatly increased antimicrobial activity compared to the monomeric peptide (Table 1). Indeed, it was previously found that the C–C and C–N terminal dimerization of anoplin via a triazole ring, formed in a reaction with additional amino acids introduced at the termini, disrupted the integrity of the bacterial membrane. (45,72) The flow cytometry experiments proved that these C–C and C–N terminal dimers of anoplin could damage the bacterial membrane. (45,72) In our work, the increased activity of anoplin dimers is most probably related to the formation of pores in the bacterial lipid membrane. (45,73) The larger net positive charge (+8e) of dimeric anoplin as compared to the monomeric form increases the binding affinity to the negatively charged bacterial membrane. The anoplin monomer is not helical but can easily adopt the α-helix near the lipids. (48) In contrast, the stapled anoplin[2-6], whose monomer is already stabilized in a helical form in the buffer solution, in a dimeric form is also helical and thus less structurally flexible, so the improvement in MIC between the stapled monomer and dimer is not so pronounced. Thus, the MIC for the anoplin[2-6] dimer is the same as for its monomeric form.
To make sure the observed effects do not arise solely from the synergy between the unlinked fragments, we investigated the combinatorial effect of non-conjugated NEO and AMK with anoplin and anoplin[2-6] on E. coli K12 MG1655 and S. aureus ATCC 29213 bacteria strains (Table 2, Figures S24–S26).
Table 2. Median FIC Determined from the Individual FIC Indexes within the Entire Checkerboard, as Well as Minimal and Maximal Values of Individual FIC Indexes
 FIC index
combinationmedianminimal valuemaximal value
E. coli K12 MG1655
NEO/anoplin0.750.502.06
NEO/anoplin[2-6]1.341.132.50
AMK/anoplin1.060.751.13
AMK/anoplin[2-6]1.101.001.25
S. aureus ATCC 29213
NEO/anoplin[2-6]0.750.531.13
AMK/anoplin[2-6]1.190.752.10
The growth inhibition concentration threshold for anoplin, especially against the S. aureus ATCC 29213 strain, was higher than 128 μM, so we did not determine the MIC as it would be irrelevant to pursue larger concentrations. Nevertheless, in the range up to 128 μM, anoplin did not show any synergistic actions with NEO or AMK on S. aureus. However, the median fractional inhibitory concentration (FIC), determined from the individual FIC indexes within the entire checkerboard, in the range of 0.5–4 confirmed indifference between anoplin[2-6] and AMK or NEO against both strains. Also, an indifferent effect was observed for the combination of anoplin with NEO or AMK against E. coli (Table 2). The minimal value of the FIC index of 0.5 appears only at one particular concentration and does not indicate synergy in the context of the whole checkerboard analysis (Figure S24). Overall, we did not observe any synergy between the molecules used for conjugation.
Data from MIC/MBC and synergy experiments (Tables 1 and 2) revealed that improved inhibitory activity of the conjugates of anoplin variants with antibiotics was a result of the antibiotic activity itself. What is more, if conjugated, these antibiotics usually showed higher MICs than antibiotics mixed with a given anoplin variant.

Hemolytic Activity

The hemolytic activity of the conjugates against the sheep RBCs is shown in Figure 2. For all conjugates with AMG (except NEO-SS-anoplin[2-6]), the hemolytic activity is negligible at the concentrations of the conjugates that inhibit bacterial growth.

Figure 2

Figure 2. Hemolytic activity of the conjugates against the sheep RBCs. Erythrocytes treated with 1% Triton-X-100 were used as a positive control (100% of hemolysis).

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However, conjugates of NEO and anoplin[2-6] show increased hemolytic activity as compared to NEO conjugates with anoplin, while the corresponding conjugates with AMK display lower hemolysis than those with NEO. NEO and AMK amino groups are protonated at pH 7 with the net charge of +6 and +4e, respectively. (11,74−76) Therefore, the higher hemolytic activity of the NEO-involving compounds could be related to the AMG charge. Still, at the MIC concentrations of these NEO-including conjugates, the hemolysis is not significant.
The anoplin[2-6]-SS-anoplin[2-6] dimer induced most changes in cell viability, with hemolytic activity above 40% at 32 μM, but it was dose-dependent, and at 4 μM (MIC of this dimer for E. coli, Table 1), the hemolysis was much lower, slightly exceeding 8%. We have previously found that monomeric anoplin[2-6] at 32 μM displayed only up to 4% hemolysis, so dimerization seems to increase the hemolytic activity for this stapled peptide. However, in general, stapled peptides can be more hemolytic than their unstapled counter-parts due to possibly different charge, hydrophobicity, and stabilized secondary structure. (40,49)

Conclusions

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We designed and synthesized a series of AMG and anoplin conjugates connected via a non-cleavable triazole linker and a cleavable disulfide bond linker. Overall, the conjugates exhibited only slightly enhanced or similar antimicrobial activity as compared to their constituents and overall low hemolytic activity. The NEO conjugates with the cleavable S–S linker (as compared to the non-cleavable linker) have only a two-fold lower MIC (so slightly increased antibacterial activity), suggesting that the peptide may interfere with the binding of AMG to the bacterial ribosome. However, at the same time, regardless of the linker, the peptide contributes to the destabilization of the bacterial cell membrane. We have previously shown that the amphipathicity and helicity of anoplin[2-6] play a crucial role in destabilizing the cell membrane, which may provide an additional entry route for the AMG. (49) This explains the observed better activity of the conjugates linked through the intracellularly degraded disulfide bond.
Our results also indicate that dimerization of peptides could be potentially beneficial without compromising toxicity. Especially, for the E. coli strains, the anoplin-SS-anoplin dimer was at least eight-fold more active than anoplin itself. This may be due to more favorable interactions with the cell wall and ease of membrane permeabilization for the dimeric form. Dimerization of the stapled anoplin did not decrease the MIC and increased hemolytic activity as compared to anoplin[2-6] alone, suggesting that either stapling or dimerization is sufficient to improve the membrane permeability by this peptide.
Our studies suggest that the conjugation of NEO and AMK with anoplin or anoplin[2-6] only modestly improves their activity against AMG-resistant strains. There is no synergistic effect of conjugation over simple mixing of peptide with antibiotic. In general, the stapling strategy shows by far the best improvement of antibacterial activity.

Materials and Methods

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Materials

All reagents, silica gel, and silica gel plates were purchased from Merck. All chemicals were of analytical or reagent grade, and all buffers were prepared using distilled water. Reactions were monitored by thin-layer chromatography, using silica gel plates (Kieselgel 60F254). Column chromatography was performed using silica gel 60 M (0.040–0.063 mm). ESI mass spectra were recorded on an LTQ Orbitrap Velos instrument (Thermo Scientific, Waltham, MA, USA). The synthesized conjugates and peptide derivatives were purified by reverse-phase high-performance liquid chromatography (RP-HPLC) on the analytical column (Knauer C18 columns, 5 μm particles, 4.6 × 250 mm) in different phases gradients (see Table S1) at a flow rate of 1.5 mL/min and wavelength of 220 nm. The mobile phase was composed of 0.1% TFA in acetonitrile (buffer A) and 0.1% TFA in water (buffer B). The presence and purity (>95%) of the obtained compounds were confirmed using RP-HPLC, mass spectrometry, and high-resolution mass spectrometry (Table S1 and Figures S4–S15). The purified products were finally dissolved in 0.1 M HCl, frozen, and lyophilized.

Peptide Synthesis

Anoplin and anoplin[2-6] were synthesized according to the procedures described by Wojciechowska et al. (49) Alkyne-anoplin, alkyne-anoplin[2-6], Cys-anoplin, Cys-anoplin[2-6] were obtained by coupling of 10-undecynoic acid or Fmoc-Cys(Mmt)-OH at the N-terminus of anoplin and anoplin[2-6]. These residues, as well as all preceding amino acids, were manually added during solid phase peptide synthesis using 9-fluorenylmethoxycarbonyl (Fmoc) strategies. Cleavage from the resin and purification of the alkyne-anoplin and alkyne-anoplin[2-6] were carried out following the previous protocols. (49) Cys-anoplin and Cys-anoplin[2-6] were conjugated on the resin (see below).

Synthesis of Protected AMG-Azide Derivatives

The azide-modified, Boc-protected NEO derivative NEO(Boc)6-N3 and the azide-modified, Boc-protected AMK derivative AMK(Boc)4-N3 were synthesized according to the procedure described in refs (27) (62), and (63).

Protected NEO-Pyridyl Disulfide Synthesis

The pyridine-substituted, disulfide NEO derivative NEO(Boc)6-SSPyr was synthesized based on the procedure reported by Wierzba et al. (58) (Scheme 1). 1,3,2′,6′,2‴,6‴-Hexa-N-(tert-butoxycarbonyl)-5″-O-(2,4,6-triisopropylbenzenesulfonyl)-neomycin (1) (62) (500 mg, 0.36 mmol, 1 equiv) was dissolved in 30 mL of ethanol, thiourea (86 mg, 1.12 mg, 3.1 equiv) was added, and the reaction mixture was refluxed overnight. The reaction progress was monitored by mass spectrometry (M = 1481.73 g/mol for the substrate and M = 1274.45 g/mol for isothiouronium cation). Next day, additional portion of thiourea (86 mg, 1.12 mg, 3.1 equiv) was added, and reflux was continued overnight. Finally, the third portion of thiourea (86 mg, 1.12 mg, 3.1 equiv) was added, and reflux was continued for the third day. When the substrate mass peak was no longer observed in the mass spectrum, the solvent was evaporated, and the crude product as an isothiouronium salt (2) was used in the next step without further purification.
The obtained NEO isothiouronium sulfonate salt (2) (0.36 mmol, 100% yield assumed) and 2-mercaptopyridine (81 mg, 0.72 mmol, 2 equiv) were dissolved in 15 mL of MeOH, and 2 M solution of MeNH2 (∼2 mL, 3.6 mmol, 10 equiv) was added. The reaction mixture was stirred at room temperature for 18 h, then evaporated with small amount of silica gel under reduced pressure. The final product NEO(Boc)6-SSPyr was isolated and purified by column chromatography using 5% solution of MeOH in CHCl3 followed by 10% solution of MeOH in CHCl3. Yield: 305 mg (63%).

Synthesis of the AMG-Peptide Conjugates by the CuAAC Reaction

The following conjugates NEO-anoplin, NEO-anoplin[2-6], AMK-anoplin, and AMK-anoplin[2-6] were synthesized using CuAAC. The CuAAC reaction components (azide-AMG/alkyne-peptide/CuSO4·5H2O/sodium l-ascorbate) were used in a molar ratio (1:2:2:8). The AMK(Boc)4-N3 or NEO(Boc)6-N3 (2 μmol) with alkyne-anoplin or alkyne-anoplin[2-6] (4 μmol) was dissolved in a solution of water and t-butanol (1 mL) (2:1, v/v). Freshly prepared water solutions of CuSO4·5H2O (4 μmol, 0.1 M) and sodium ascorbate (32 μmol, 0.5 M) were added. The mixture was stirred at 30 °C in a thermoshaker at 600 rpm for 24 h. After lyophilization, the removal of the Boc-protective groups from AMG derivatives was performed by treatment in a solution of TFA/triisopropylsilane (TIPS)/m-cresol (95:2.5:2.5; v/v/v) and mixed for 30 min. After adding cold diethyl ether, the conjugates were precipitated, decanted, then dissolved in water, lyophilized, and subsequently purified by analytical RP-HPLC.

Synthesis of AMG-Peptide Conjugates by Disulfide Bond Formation

Conjugation of NEO-SSPyr with Cys-anoplin or Cys-anoplin[2-6] by disulfide bond formation was performed on the resin (TentaGel S RAM resin; amine groups loading of 0.24 mmol/g). (66) After the synthesis of peptides, the Fmoc deprotection from the N-terminus was carried out using 20% piperidine in dimethylformamide (DMF) for two cycles in 10 min. The Mmt protective group on Cys was removed by adding the solution of dichloromethane (DCM)/TFA/TIPS (94:1:5) for five cycles in 2 min. (77) The resins were washed with DCM and DMF solution under a nitrogen atmosphere. Three-fold molar excess of NEO-SSPyr was dissolved in the DMF/N-methylpyrrolidone (NMP); 1:1; v/v and mixed for 3 h. Coupling was repeated with a fresh portion of NEO-SSPyr in a two-fold molar excess and carried out for another 3 h. Removal of the protecting groups and cleavage of the conjugates from the resin were performed by treatment with a TFA/water/TIPS (95:2.5:2.5; v/v/v) mixture for 3 h. Conjugates were precipitated by adding cold diethyl ether, decanted, then dissolved in water, lyophilized, and finally purified by analytical RP-HPLC.

Synthesis of Peptide Dimers

Cys-anoplin and Cys-anoplin[2-6] were cleaved from the resin by treatment with a TFA/phenol/TIPS/water (95:2:2:1; v/v/v/v) for 3 h. By adding cold diethyl ether, the peptides with the free thiol group were precipitated, decanted, and dissolved in water. The anoplin-SS-anoplin and anoplin[2-6]-SS-anoplin[2-6] peptide dimers were formed in the solution of water under an air atmosphere spontaneously by disulfide bond formation. (78) Finally, the products were purified by analytical PR-HPLC and lyophilized.

Antibacterial Activity Determination

The MIC values were determined as follows. Bacteria were first cultured overnight in 2 mL of lysogeny broth (LB, VWR Chemicals) at 37 °C with shaking. Next, 20 μL of overnight culture was transferred into 2 mL of Miller-Hinton broth (MHB, Difco) medium and further cultured at 37 °C with shaking until the culture reached OD600 = 0.3. Subsequently, the culture was diluted 1:100 in a fresh MHB medium, and aliquots of 50 μL were mixed with 50 μL of previously prepared dilutions of the tested compound in MHB on a transparent flat-bottom 96-well plate (Nest). The plate was then sealed with transparent foil (Titer-Tops) and incubated for 20 h, at 37 °C with shaking. Following incubation, optical density at 600 nm was measured using a Tecan Sunrise plate reader. Growth inhibition was determined by comparing the given sample with untreated culture (growth control─GC) with MHB alone (sterility control─SC) as an additional reference. The experiment was conducted in at least two biological replicates of two technical replicates each. Statistical significance was determined by the two-way ANOVA test using GraphPad Prism 9 software.
The MBC values were determined by diluting wells from the MIC experiment plate in fresh MHB medium. Dilutions of 10-, 100-, and 1000-times were prepared for the MIC well and up to two-folds higher than MIC concentrations of a given compound. Dilutions were made on a transparent flat-bottom 96-well plate (Nest), which was then sealed and incubated for 24 h, at 37 °C with shaking. The growth of a given sample well was compared with GC and SC controls. A particular concentration of a compound was considered bactericidal if no growth was observed for at least 100- and 1000-times dilutions.

Evaluation of the Synergistic Effect

The synergy between the compounds was assessed using the checkerboard method in a similar way as mentioned in our previous study. (79,80) Bacteria were first cultured overnight in 2 mL of LB (VWR Chemicals) at 37 °C with shaking. Next, 20 μL of overnight culture was transferred into 2 mL of MHB medium and further cultured at 37 °C with shaking until the culture reached OD600 = 0.3. Subsequently, culture was diluted 1:200 in a fresh MHB medium, and aliquots of 90 μL were mixed with 10 μL of previously prepared dilutions of tested compounds in MHB on a transparent flat-bottom 96-well plate (Nest). The plate was then sealed with transparent adhesive foil (Titer-Tops) and incubated for 20 h, at 37 °C with shaking. Following incubation, optical density at 600 nm was measured using the Tecan Sunrise plate reader. Growth inhibition was determined by comparing the given sample with untreated culture (GC) with MHB alone (SC) as an additional reference. The FIC index was calculated for the first cell within each row and column where growth inhibition was observed. The following formula was used
FICi=FICa+FICb=(CaMICa)+(CbMICb)
Ca, Cb─concentration of the agent in combination, and MICa, MICb─MICs for agent a and agent b alone.
Then, the median FIC was determined for the entire checkerboard. In addition, the minimal and maximal values were distinguished (Table 2). The FIC values ≤ 0.5 were considered as synergy, 0.5< and ≤4 as indifference, and >4 as antagonism.

Hemolytic Activity

The hemolytic activity of the peptides against intact erythrocytes was tested using sheep fresh RBCs. The 200 μL of sheep RBCs was washed three times with PBS buffer (10 mM, pH 7.4) at 3500 rpm for 5 min. Then, the cells were diluted in 10 mL of PBS buffer, divided into 200 μL of aliquots in 1.5 mL tubes, and pelleted by centrifugation. The concentration series of AMG–AMP conjugates and peptide dimers was prepared in PBS buffer. 200 μL of each concentration (32, 16, 8, 4, and 2 μM) was added to RBC suspension and incubated for 30 min (165 rpm, 37 °C). Finally, the cells with each incubated sample were centrifuged (3500 rpm, 5 min). Then, 100 μL of the supernatant from each tube was collected into a clear 96-well plate. The sample absorbance was measured at 405 nm using a spectrophotometer (Microplate Reader BioTek, Winooski, VT, United States). The hemolytic activity, as the percentage of hemolysis, was calculated from the following equation
%hemolysis=(A−A0)(A100−A0)×100%
where A0 is the absorbance intensity of the RBC in buffer (background), A is the absorbance intensity of the RBS in the presence of peptides, and A100 is the absorbance intensity of the Triton X-100.
The erythrocyte suspension treated with 1% Triton X-100 served as a positive control, and the untreated suspension was used as a negative control. Tests were performed with duplicate samples, and the average values of two independent measurements were recorded..

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c02071.

  • MS spectra and RP-HPLC chromatograms of AMG-derivatives, peptide, peptide-derivatives, AMG–AMP conjugates, and peptide dimers; synthesis schemes of the AMG–peptide conjugates; optical density (OD600) as a measure of E. coli K-12 MG1655, E. coli WR 3551/98, S. aureus ATCC 29213, and S. aureus BAA-1720 MRSA growth after 20 h incubation with AMG–AMP conjugates, peptide dimers, amikacin, and neomycin; and typical checkerboard test combinations determined for E. coli K12 MG1655 and S. aureus ATCC 29213 (PDF)

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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Authors
  • Authors
    • Julia Macyszyn - Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;  Orcidhttps://orcid.org/0000-0002-2501-4391
    • Michał Burmistrz - Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;  Orcidhttps://orcid.org/0000-0002-2350-0003
    • Adam Mieczkowski - Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
  • Author Contributions

    The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. J.M. synthesized the peptides and AMG–AMP conjugates and performed the hemolytic assays. M.B. performed the antibacterial activity assays. A.M. synthesized the AMG-modified derivatives. M.W. designed the sequences of the AMG–AMP conjugates. J.M. wrote the initial manuscript draft. M.W., M.B., A.M., and J.T. revised the manuscript. M.W. and J.T. supervised the project. All authors analyzed and discussed the results and agreed to the published version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We acknowledge support from the National Science Centre, Poland (Sonata 2019/35/D/NZ1/01957 to J.M. and M.W. and 2020/37/B/NZ1/02904 to M.B. and J.T.).

Abbreviations

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AMG

aminoglycosides

AMK

amikacin

AMP

antimicrobial peptides

Boc

tert-butyloxycarbonyl

CuAAC

copper-catalyzed alkyne–azide cycloaddition

E. coli

Escherichia coli

DMF

dimethylformamide

FIC

fractional inhibitory concentration

Fmoc

9-fluorenylmethoxycarbonyl

NEO

neomycin

NMP

N-methylpyrrolidone

MBC

minimal bactericidal concentration

MIC

minimal inhibitory concentration

Mmt

methoxytrityl

RP-HPLC

reverse-phase high-performance liquid chromatography

S. aureus

Staphylococcus aureus

TFA

trifluoroacetic acid

TIPS

triisopropylsilane

References

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This article references 80 other publications.

  1. 1
    Venkatesan, P. WHO 2020 report on the antibacterial production and development pipeline. Lancet Microbe 2021, 2, e239  DOI: 10.1016/s2666-5247(21)00124-5
    [Crossref], [PubMed], Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Sansom, C. Where are the next generation of antibiotics going to come from? https://www.chemistryworld.com/features/the-antibiotic-countdown/3008544.article (accessed Nov 08, 2022).
    Google Scholar
    There is no corresponding record for this reference.
  3. 3
    Ghosh, S.; Bornman, C.; Zafer, M. M. Antimicrobial Resistance Threats in the emerging COVID-19 pandemic: Where do we stand?. J. Infect. Public Health 2021, 14, 555– 560,  DOI: 10.1016/j.jiph.2021.02.011
    [Crossref], [PubMed], [CAS], Google Scholar
    3
    Antimicrobial Resistance Threats in the emerging COVID-19 pandemic: Where do we stand?
    Ghosh Soumya; Bornman Charne; Zafer Mai M
    Journal of infection and public health (2021), 14 (5), 555-560 ISSN:.
    Antimicrobial resistance (AMR) continues to exert a substantial toll on the global health and world economy and is now expected to be hidden by COVID-19 for a while. The wrong consumption of antibiotics during the COVID-19 pandemic will raise disastrous effects on AMR management and antibiotic stewardship programs. This is related to the concerns extrapolated due to an increase in mortality rates in patients with bacterial coinfections. Importantly, the immune system of COVID-19 patients in regions with high AMR may be fighting on two fronts altogether, the virus and MDR bacteria. Current control policies to manage AMR and prioritization of antibiotic stewardship plans are mandatory during this pandemic. This review aims to discuss the rising concerns of the excess use of antibiotics in COVID-19 patients highlighting the role of bacterial coinfections in these patients. Types of prescribed antibiotics and the development of antibiotic resistance is addressed as well.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3sbgsVaktw%253D%253D&md5=a2288e6724eefba679941424d22cd9eb
  4. 4
    Ma, E. S. K.; Kung, K. H.; Chen, H. Combating antimicrobial resistance during the COVID-19 pandemic. Hong Kong Med. J. 2021, 27, 396– 398,  DOI: 10.12809/hkmj215124
    [Crossref], [PubMed], [CAS], Google Scholar
    4
    Combating antimicrobial resistance during the COVID-19 pandemic
    Ma E S K; Ma E S K; Kung K H; Chen H
    Hong Kong medical journal = Xianggang yi xue za zhi (2021), 27 (6), 396-398 ISSN:1024-2708.
    There is no expanded citation for this reference.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2cfjvVensg%253D%253D&md5=725dc36fb20fc9bf39404728db362173
  5. 5
    Krause, K. M.; Serio, A. W.; Kane, T. R.; Connolly, L. E. Aminoglycosides : An Overview. Cold Spring Harbor Perspect. Med. 2016, 6, a027029,  DOI: 10.1101/cshperspect.a027029
    [Crossref], [PubMed], [CAS], Google Scholar
    5
    Aminoglycosides: an overview
    Krause, Kevin M.; Serio, Alisa W.; Kane, Timothy R.; Connolly, Lynn E.
    Cold Spring Harbor Perspectives in Medicine (2016), 6 (6), a027029/1-a027029/19CODEN: CSHPFV; ISSN:2157-1422. (Cold Spring Harbor Laboratory Press)
    Aminoglycosides are natural or semisynthetic antibiotics derived from actinomycetes. They were among the first antibiotics to be introduced for routine clin. use and several examples have been approved for use in humans. They found widespread use as first-line agents in the early days of antimicrobial chemotherapy, but were eventually replaced in the 1980s with cephalosporins, carbapenems, and fluoroquinolones. Aminoglycosides synergize with a variety of other antibacterial classes, which, in combination with the continued increase in the rise of multidrug-resistant bacteria and the potential to improve the safety and efficacy of the class through optimized dosing regimens, has led to a renewed interest in these broad-spectrum and rapidly bactericidal antibacterials.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXns1ylsbs%253D&md5=675d7f4c769fdcc681171a121e5aa09e
  6. 6
    Houghton, J. L.; Green, K. D.; Chen, W.; Garneau-Tsodikova, S. The future of aminoglycosides: The end or renaissance?. ChemBioChem 2010, 11, 880– 902,  DOI: 10.1002/cbic.200900779
    [Crossref], [PubMed], [CAS], Google Scholar
    6
    The Future of Aminoglycosides: the End or Renaissance?
    Houghton, Jacob L.; Green, Keith D.; Chen, Wenjing; Garneau-Tsodikova, Sylvie
    ChemBioChem (2010), 11 (7), 880-902CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Although aminoglycosides were used as antibacterials for decades, their use was hindered by their inherent toxicity and the resistance that has emerged to these compds. It seems that such issues have relegated a formerly front-line class of antimicrobials to the proverbial back shelf. However, recent advances have demonstrated that novel aminoglycosides have a potential to overcome resistance as well as to be used to treat HIV-1 and even human genetic disorders, with abrogated toxicity. It is not the end for aminoglycosides, but rather, the challenges faced by researchers have led to ingenuity and a change in how we view this class of compds., a renaissance.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlsVOqtrc%253D&md5=22365625c73ebefd449c4d01218191ff
  7. 7
    Becker, B.; Cooper, M. A. Aminoglycoside antibiotics in the 21st century. ACS Chem. Biol. 2013, 8, 105– 115,  DOI: 10.1021/cb3005116
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    7
    Aminoglycoside Antibiotics in the 21st Century
    Becker, Bernd; Cooper, Matthew A.
    ACS Chemical Biology (2013), 8 (1), 105-115CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    A review. Aminoglycoside antibiotics were among the first antibiotics discovered and used clin. Although they have never completely fallen out of favor, their importance has waned due to the emergence of other broad-spectrum antibiotics with fewer side effects. Today, with the dramatically increasing rate of infections caused by multidrug-resistant bacteria, focus has returned to aminoglycoside antibiotics as one of the few remaining treatment options, particularly for Gram-neg. pathogens. Although the mechanisms of resistance are reasonably well understood, our knowledge about the mode of action of aminoglycosides is still far from comprehensive. In the face of emerging bacterial infections that are virtually untreatable, it is time to have a fresh look at this old class to reinvigorate the struggle against multidrug-resistant pathogens.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFygtLzM&md5=67c9e67ef40a2855f6bba4c4f9e52f24
  8. 8
    Schatz, A.; Bugie, E.; Waksman, S. A.; Hanssen, A. D.; Patel, R.; Osmon, D. R. . The Classic: Streptomycin, a Substance Exhibiting Antibiotic Activity against Gram-Positive and Gram-Negative Bacteria. Clin. Orthop. Relat. Res. 2005, 437, 3– 6,  DOI: 10.1097/01.blo.0000175887.98112.fe
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  9. 9
    Wang, N.; Luo, J.; Deng, F.; Huang, Y.; Zhou, H. Antibiotic Combination Therapy: A Strategy to Overcome Bacterial Resistance to Aminoglycoside Antibiotics. Front. Pharmacol. 2022, 13, 1– 15,  DOI: 10.3389/fphar.2022.839808
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Bera, S.; Mondal, D.; Palit, S.; Schweizer, F. Structural modifications of the neomycin class of aminoglycosides. MedChemComm 2016, 7, 1499– 1534,  DOI: 10.1039/c6md00079g
    [Crossref], [CAS], Google Scholar
    10
    Structural modifications of the neomycin class of aminoglycosides
    Bera, Smritilekha; Mondal, Dhananjoy; Palit, Subhadeep; Schweizer, Frank
    MedChemComm (2016), 7 (8), 1499-1534CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    A review. Clin. used potent broad spectrum bactericidal aminoglycoside (AG) antibiotics have suffered diminished use due to dose-related toxicity and rapid emergence of resistance. To overcome these shortfalls, researchers have performed many structural modifications to the aminoglycoside scaffold. The motivation behind the development of novel aminoglycoside analogs is in part caused by the inability to discover novel antibiotics with new modes of action esp. against Gram-neg. bacteria. As AGs are composed of highly functionalised polycationic oligosaccharides carrying several hydroxy and amino functional groups with an incorporated streptamine unit, numerous synthetic approaches for their fabrication and revitalization have been articulated. Impressive endeavours and advancements made in this direction by researchers across the globe have been well documented in a large vol. of literature. The objective of this review article is to summarize the recent progress in this field in a comprehensive manner paying special attention to the chem. of structurally related neomycin, paromomycin and neamine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptFygt7c%253D&md5=c5b65976703acf7d3afb010d5862b5a9
  11. 11
    Trylska, J.; Kulik, M. Interactions of aminoglycoside antibiotics with rRNA. Biochem. Soc. Trans. 2016, 44, 987– 993,  DOI: 10.1042/bst20160087
    [Crossref], [PubMed], [CAS], Google Scholar
    11
    Interactions of aminoglycoside antibiotics with rRNA
    Trylska, Joanna; Kulik, Marta
    Biochemical Society Transactions (2016), 44 (4), 987-993CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)
    Aminoglycoside antibiotics are protein synthesis inhibitors applied to treat infections caused mainly by aerobic Gram-neg. bacteria. Due to their adverse side effects they are last resort antibiotics typically used to combat pathogens resistant to other drugs. Aminoglycosides target ribosomes. We describe the interactions of aminoglycoside antibiotics contg. a 2-deoxystreptamine (2-DOS) ring with 16S rRNA. We review the computational studies, with a focus on mol. dynamics (MD) simulations performed on RNA models mimicking the 2-DOS aminoglycoside binding site in the small ribosomal subunit. We also briefly discuss thermodn. of interactions of these aminoglycosides with their 16S RNA target.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlCju7rN&md5=8040912c76491f5a7e376de1adbec5f8
  12. 12
    Kotra, L. P.; Haddad, J.; Mobashery, S. Aminoglycosides: Perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob. Agents Chemother. 2000, 44, 3249– 3256,  DOI: 10.1128/aac.44.12.3249-3256.2000
    [Crossref], [PubMed], [CAS], Google Scholar
    12
    Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance
    Kotra, Lakshmi P.; Haddad, Jalal; Mobashery, Shahriar
    Antimicrobial Agents and Chemotherapy (2000), 44 (12), 3249-3256CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    A review with 57 refs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhs1Kisbc%253D&md5=516edd439b0dbf0709ffd013d05648f8
  13. 13
    Fourmy, D.; Recht, M. I.; Puglisi, J. D. Binding of neomycin-class aminoglycoside antibiotics to the A-site of 16 S rRNA. J. Mol. Biol. 1998, 277, 347– 362,  DOI: 10.1006/jmbi.1997.1552
    [Crossref], [PubMed], [CAS], Google Scholar
    13
    Binding of neomycin-class aminoglycoside antibiotics to the A-site of 16 S rRNA
    Fourmy, Dominique; Recht, Michael I.; Puglisi, Joseph D.
    Journal of Molecular Biology (1998), 277 (2), 347-362CODEN: JMOBAK; ISSN:0022-2836. (Academic Press Ltd.)
    Aminoglycoside antibiotics that bind to rRNA in the aminoacyl-tRNA site (A-site) cause misreading of the genetic code and inhibit translocation. We have recently solved the structure of an A-site RNA-paromomycin complex. The structure suggested that rings I and II, common to all aminoglycosides that bind to the A-site, are the min. motif for specific ribosome binding to affect translation. This hypothesis was tested biochem. and with a detailed comparative NMR study of interaction of the aminoglycosides paromomycin, neomycin, ribostamycin, and neamine with the A-site RNA. Our NMR data show that rings I and II of neomycin-class aminoglycosides are sufficient to confer specificity to the binding of the antibiotics to the model A-site RNA. Neomycin, paromomycin, ribostamycin and neamine bind in the major groove of the A-site RNA in a unique binding pocket formed by non-canonical base pairs and a bulged nucleotide. Similar NMR properties of the RNA and the diverse antibiotics within the different complexes formed with neomycin, paromomycin, ribostamycin and neamine suggest similar structures for these complexes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXislalsLw%253D&md5=b8cf9da04ec22664fc7a655b7a4413a0
  14. 14
    Maxwell, A.; Ghate, V.; Aranjani, J.; Lewis, S. Breaking the barriers for the delivery of amikacin: Challenges, strategies, and opportunities. Life Sci. 2021, 284, 119883,  DOI: 10.1016/j.lfs.2021.119883
    [Crossref], [PubMed], [CAS], Google Scholar
    14
    Breaking the barriers for the delivery of amikacin: Challenges, strategies, and opportunities
    Maxwell, Amala; Ghate, Vivek; Aranjani, Jesil; Lewis, Shaila
    Life Sciences (2021), 284 (), 119883CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
    A review. Hypodermic delivery of amikacin is a widely adopted treatment modality for severe infections, including bacterial septicemia, meningitis, intra-abdominal infections, burns, postoperative complications, and urinary tract infections in both paediatric and adult populations. In most instances, the course of treatment requires repeated bolus doses of amikacin, prolonged hospitalization, and the presence of a skilled healthcare worker for administration and continuous therapeutic monitoring to manage the severe adverse effects. Amikacin is hydrophilic and exhibits a short half-life, which further challenges the delivery of sufficient systemic concns. when administered by the oral or transdermal route. In this purview, the exploitation of novel controlled and sustained release drug delivery platforms is warranted. Furthermore, it has been shown that novel delivery systems are capable of increasing the antibacterial activity of amikacin at lower doses when compared to the conventional formulations and also aid in overcoming the development of drug-resistance, which currently is a significant threat to the healthcare system worldwide. The current review presents a comprehensive overview of the developmental history of amikacin, the mechanism of action in virulent strains as well as the occurrence of resistance, and various emerging drug delivery solns. developed both by the academia and the industry. The examples outlined within the review provides significant pieces of evidence on novel amikacin formulations in the field of antimicrobial research paving the path for future therapeutic interventions that will result in improved clin. outcome.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvVait73P&md5=0265ef382131d76655e550ba5dc91caf
  15. 15
    Vakulenko, S. B.; Mobashery, S. Versatility of aminoglycosides and prospects for their future. Clin. Microbiol. Rev. 2003, 16, 430– 450,  DOI: 10.1128/cmr.16.3.430-450.2003
    [Crossref], [PubMed], [CAS], Google Scholar
    15
    Versatility of aminoglycosides and prospects for their future
    Vakulenko, Sergei B.; Mobashery, Shahriar
    Clinical Microbiology Reviews (2003), 16 (3), 430-450CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
    A review. Aminoglycoside antibiotics have had a major impact on our ability to treat bacterial infections for the past half century. Whereas the interest in these versatile antibiotics continues to be high, their clin. utility has been compromised by widespread instances of resistance. The multitude of mechanisms of resistance is disconcerting but also illuminates how Nature can manifest resistance when bacteria are confronted by antibiotics. This article reviews the most recent knowledge about the mechanisms of aminoglycoside action and the mechanisms of resistance to these antibiotics.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmsV2qt7k%253D&md5=896987be9a8aa808dc6c31fa97a93d12
  16. 16
    Tevyashova, A. N.; Shapovalova, K. S. Potential for the Development of a New Generation of Aminoglycoside Antibiotics. Pharm. Chem. J. 2021, 55, 860– 875,  DOI: 10.1007/s11094-021-02510-0
    [Crossref], [PubMed], [CAS], Google Scholar
    16
    Potential for the Development of a New Generation of Aminoglycoside Antibiotics
    Tevyashova, A. N.; Shapovalova, K. S.
    Pharmaceutical Chemistry Journal (2021), 55 (9), 860-875CODEN: PCJOAU; ISSN:0091-150X. (Springer)
    A review. The present review summarizes recent publications devoted to aminoglycosides that study the main types of resistance to antibiotics of this class and the main directions of chem. modification aimed at overcoming the resistance or changing the spectrum of biol. activity. Conjugates of aminoglycosides with various pharmacophores including amino acids, peptides, peptide nucleic acids, nucleic bases, and several other biol. active mols. and modifications resulting in other types of biol. activity of this class of antibiotics are described. It is concluded that a promising research direction aimed at increasing the activity of antibiotics against resistant strains is the search for selective inhibitors of aminoglycoside-modifying enzymes. This would allow renewal of the use of antibiotics already meeting widespread resistance and would increase the potential of a new generation of antibiotics.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtVOmu7g%253D&md5=0ae50800fbf957aa9d73d9607750d14a
  17. 17
    Udumula, V.; Ham, Y. W.; Fosso, M. Y.; Chan, K. Y.; Rai, R.; Zhang, J.; Li, J.; Chang, C. W. T. Investigation of antibacterial mode of action for traditional and amphiphilic aminoglycosides. Bioorg. Med. Chem. Lett. 2013, 23, 1671– 1675,  DOI: 10.1016/j.bmcl.2013.01.073
    [Crossref], [PubMed], [CAS], Google Scholar
    17
    Investigation of antibacterial mode of action for traditional and amphiphilic aminoglycosides
    Udumula, Venkatareddy; Ham, Young Wan; Fosso, Marina Y.; Chan, Ka Yee; Rai, Ravi; Zhang, Jianjun; Li, Jie; Chang, Cheng-Wei Tom
    Bioorganic & Medicinal Chemistry Letters (2013), 23 (6), 1671-1675CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Aminoglycoside represents a class of versatile and broad spectrum antibacterial agents. In an effort to revive the antibacterial activity against aminoglycoside resistant bacteria, our lab. has developed two new classes of aminoglycoside, pyranmycin and amphiphilic neomycin (NEOF004). The former resembles the traditional aminoglycoside, neomycin. The latter, albeit derived from neomycin, appears to exert antibacterial action via a different mode of action. In order to discern that these aminoglycoside derivs. have distinct antibacterial mode of action, RNA-binding affinity and fluorogenic dye were employed. These studies, together with our previous investigation, confirm that pyranmycin exhibit the traditional antibacterial mode of action of aminoglycosides by binding toward the bacterial rRNA. On the other hand, the amphiphilic neomycin, NEOF004 disrupts the bacterial cell wall. In a broader perspective, it verifies that structurally modified neomycin can exert different antibacterial mode of action leading to the revival of activity against aminoglycoside resistant bacteria.
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  18. 18
    Aradi, K.; Di Giorgio, A.; Duca, M. Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond. Chem.─Eur. J. 2020, 26, 12273– 12309,  DOI: 10.1002/chem.202002258
    [Crossref], [PubMed], [CAS], Google Scholar
    18
    Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond
    Aradi, Klara; Di Giorgio, Audrey; Duca, Maria
    Chemistry - A European Journal (2020), 26 (54), 12273-12309CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Natural aminoglycosides are therapeutically useful antibiotics and very efficient RNA ligands. They are oligosaccharides that contain several ammonium groups able to interfere with the translation process in prokaryotes upon binding to bacterial rRNA, and thus, impairing protein synthesis. Even if aminoglycosides are commonly used in therapy, these RNA binders lack selectivity and are able to bind to a wide no. of RNA sequences/structures. This is one of the reasons for their toxicity and limited applications in therapy. At the same time, the ability of aminoglycosides to bind to various RNAs renders them a great source of inspiration for the synthesis of new binders with improved affinity and specificity toward several therapeutically relevant RNA targets. Thus, a no. of studies have been performed on these complex and highly functionalized compds., leading to the development of various synthetic methodologies toward the synthesis of conjugated aminoglycosides. The aim of this review is to highlight recent progress in the field of aminoglycoside conjugation, paying particular attention to modifications performed toward the improvement of affinity and esp. to the selectivity of the resulting compds. This will help readers to understand how to introduce a desired chem. modification for future developments of RNA ligands as antibiotics, antiviral, and anticancer compds.
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  19. 19
    Chandrika, T. N.; Garneau-Tsodikova, S. Comprehensive Review of Chemical Strategies for the Preparation of New Aminoglycosides and their Biological Activities. Chem. Soc. Rev. 2018, 47, 1189– 1249,  DOI: 10.1039/c7cs00407a
    [Crossref], [PubMed], Google Scholar
    There is no corresponding record for this reference.
  20. 20
    Kato, T.; Yang, G.; Teo, Y.; Juskeviciene, R.; Perez-Fernandez, D.; Shinde, H. M.; Salian, S.; Bernet, B.; Vasella, A.; Böttger, E. C.; Crich, D. Synthesis and Antiribosomal Activities of 4′-O-6′-O-4″-O-4′,6′-O- and 4″,6″-O-Derivatives in the Kanamycin Series Indicate Differing Target Selectivity Patterns between the 4,5- and 4,6-Series of Disubstituted 2-Deoxystreptamine Aminoglycoside Antibiotics. ACS Infect. Dis. 2015, 1, 479– 486,  DOI: 10.1021/acsinfecdis.5b00069
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    20
    Synthesis and Antiribosomal Activities of 4'-O-, 6'-O-, 4''-O-, 4',6'-O- and 4'',6''-O-Derivatives in the Kanamycin Series Indicate Differing Target Selectivity Patterns between the 4,5- and 4,6-Series of Disubstituted 2-Deoxystreptamine Aminoglycoside Antibiotics
    Kato, Takayuki; Yang, Guanyu; Teo, Youjin; Juskeviciene, Reda; Perez-Fernandez, Deborah; Shinde, Harish M.; Salian, Sumanth; Bernet, Bruno; Vasella, Andrea; Bottger, Erik C.; Crich, David
    ACS Infectious Diseases (2015), 1 (10), 479-486CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
    Chem. for the efficient modification of the kanamycin class of 4,6-aminoglycosides at the 4'-position is presented. In all kanamycins but kanamycin B, 4'-O-alkylation is strongly detrimental to antiribosomal and antibacterial activity. Ethylation of kanamycin B at the 4''-position entails little loss of antiribosomal and antibacterial activity, but no increase of ribosomal selectivity. These results are contrasted with those for the 4,5-aminoglycosides, where 4'-O-alkylation of paromomycin causes only a minimal loss of activity but results in a significant increase in selectivity with a concomitant loss of ototoxicity.
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  21. 21
    Zhang, J.; Keller, K.; Takemoto, J. Y.; Bensaci, M.; Litke, A.; Czyryca, P. G.; Chang, C. W. T. Synthesis and combinational antibacterial study of 5″-modified neomycin. J. Antibiot. 2009, 62, 539– 544,  DOI: 10.1038/ja.2009.66
    [Crossref], [PubMed], [CAS], Google Scholar
    21
    Synthesis and combinational antibacterial study of 5''-modified neomycin
    Zhang, Jianjun; Keller, Katherine; Takemoto, Jon Y.; Bensaci, Mekki; Litke, Anthony; Czyryca, Przemyslaw Greg; Chang, Cheng-Wei Tom
    Journal of Antibiotics (2009), 62 (10), 539-544CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
    A library of 5''-modified neomycin derivs. were synthesized for an antibacterial structure-activity optimization strategy. Two leads exhibited prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clin. used antibiotics. Significant synergistic activities were obsd., which may lead to the development of novel therapeutic practices in the battle against infectious bacteria.
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  22. 22
    Zhang, J.; Chiang, F. I.; Wu, L.; Czyryca, P. G.; Li, D.; Chang, C. W. T. Surprising alteration of antibacterial activity of 5″-modified neomycin against resistant bacteria. J. Med. Chem. 2008, 51, 7563– 7573,  DOI: 10.1021/jm800997s
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    22
    Surprising Alteration of Antibacterial Activity of 5''-Modified Neomycin against Resistant Bacteria
    Zhang, Jianjun; Chiang, Fang-I.; Wu, Long; Czyryca, Przemyslaw Greg; Li, Ding; Chang, Cheng-Wei Tom
    Journal of Medicinal Chemistry (2008), 51 (23), 7563-7573CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A facile synthetic protocol for the prodn. of neomycin B derivs. with various modifications at the 5'' position has been developed. The structural activity relation (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymic and mol. modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivs. show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivs. against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clin. used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biol. and antimicrobial activities can be obtained by chem. modifications of old drugs.
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  23. 23
    Martin, C.; Bonnet, M.; Patino, N.; Azoulay, S.; Di Giorgio, A.; Duca, M. Design, synthesis and evaluation of neomycin-imidazole conjugates for RNA cleavage. Chempluschem 2022, 87, 49– 58,  DOI: 10.1002/cplu.202200250
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  24. 24
    Bera, S.; Zhanel, G. G.; Schweizer, F. Design, synthesis, and antibacterial activities of neomycin-lipid conjugates: Polycationic lipids with potent gram-positive activity. J. Med. Chem. 2008, 51, 6160– 6164,  DOI: 10.1021/jm800345u
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    24
    Design, Synthesis, and Antibacterial Activities of Neomycin-Lipid Conjugates: Polycationic Lipids with Potent Gram-Positive Activity
    Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
    Journal of Medicinal Chemistry (2008), 51 (19), 6160-6164CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Aminoglycoside antibiotics and cationic detergents constitute two classes of important drugs and antiseptics. Their bacterial efficacy has decreased recently due to antibiotic resistance. We have synthesized aminoglycoside-lipid conjugates in which the aminoglycoside neomycin forms the cationic headgroup of a polycationic detergent. Our results show that neomycin-C16 and neomycin-C20 conjugates exhibit strong Gram-pos. activity but reduced Gram-neg. activity. The MIC of neomycin-C16 (C20) conjugates against methicillin-resistant Staphylococcus aureus (MRSA) is comparable to known antiseptics.
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  25. 25
    Bera, S.; Zhanel, G. G.; Schweizer, F. Evaluation of amphiphilic aminoglycoside-peptide triazole conjugates as antibacterial agents. Bioorg. Med. Chem. Lett. 2010, 20, 3031– 3035,  DOI: 10.1016/j.bmcl.2010.03.116
    [Crossref], [PubMed], [CAS], Google Scholar
    25
    Evaluation of amphiphilic aminoglycoside-peptide triazole conjugates as antibacterial agents
    Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
    Bioorganic & Medicinal Chemistry Letters (2010), 20 (10), 3031-3035CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    The solid- and soln.-phase synthesis of amphiphilic aminoglycoside-peptide triazole conjugates (APTCs) accessed by copper(I)-catalyzed 1,3-dipolar cycloaddn. reaction between a hydrophobic and ultrashort peptide-based alkyne and a neomycin B- or kanamycin A-derived azide is presented. Antibacterial evaluation demonstrates that the antibacterial potency is affected by the nature of the peptide component. Several APTCs exhibit superior activity against neomycin B- and kanamycin A-resistant strains when compared to their parent aminoglycoside while displaying reduced activity against neomycin B- and kanamycin A-susceptible strains.
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  26. 26
    Bera, S.; Zhanel, G. G.; Schweizer, F. Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates. Carbohydr. Res. 2011, 346, 560– 568,  DOI: 10.1016/j.carres.2011.01.015
    [Crossref], [PubMed], [CAS], Google Scholar
    26
    Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates
    Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
    Carbohydrate Research (2011), 346 (5), 560-568CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
    Amphiphilic lysine-ligated neomycin B building blocks were prepd. by reductive amination of a protected C5''-modified neomycin B-based aldehyde and side chain-unprotected lysine or lysine-contg. peptides. It was demonstrated that a suitably protected lysine-ligated neomycin B conjugate (NeoK) serves as a building block for peptide synthesis, enabling incorporation of aminoglycoside binding sites into peptides. Antibacterial testing of three amphiphilic lysine-ligated neomycin B conjugates against a representative panel of Gram-pos. and Gram-neg. strains demonstrates that C5''-modified neomycin-lysine conjugate retains antibacterial activity. However, in most cases the lysine-ligated neomycin B analogs display reduced potency against Gram-pos. strains when compared to unmodified neomycin B or unligated peptide. An exception is MRSA where an eightfold enhancement was obsd. When compared to unmodified neomycin B, the prepd. lysine-neomycin conjugates exhibited a 4-8-fold enhanced Gram-neg. activity against Pseudomonas aeruginosa and up to 12-fold enhanced activity was obsd. when compared to unligated ref. peptides.
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  27. 27
    Fair, R. J.; McCoy, L. S.; Hensler, M. E.; Aguilar, B.; Nizet, V.; Tor, Y. Singly modified amikacin and tobramycin derivatives show increased rRNA A-site binding and higher potency against resistant bacteria. ChemMedChem 2014, 9, 2164– 2171,  DOI: 10.1002/cmdc.201402175
    [Crossref], [PubMed], [CAS], Google Scholar
    27
    Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A-Site Binding and Higher Potency against Resistant Bacteria
    Fair, Richard J.; McCoy, Lisa S.; Hensler, Mary E.; Aguilar, Bernice; Nizet, Victor; Tor, Yitzhak
    ChemMedChem (2014), 9 (9), 2164-2171CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Semisynthetic derivs. of the clin. useful aminoglycosides tobramycin and amikacin were prepd. by selectively modifying their 6'' positions with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A-site was probed using an in vitro FRET-based assay, and their antibacterial activities against several resistant strains (e.g., Pseudomonas aeruginosa, Klebsiella pneumonia, MRSA) were quantified by detg. min. inhibitory concns. (MICs). The most potent derivs. were evaluated for their eukaryotic cytotoxicity. Most analogs displayed higher affinity for the bacterial A-site than the parent compds. Although most tobramycin analogs exhibited no improvement in antibacterial activity, several amikacin analogs showed potent and broad-spectrum antibacterial activity against resistant bacteria. Derivs. tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compds.
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  28. 28
    Shai, Y. Mode of action of membrane active antimicrobial peptides. Biopolymers 2002, 66, 236– 248,  DOI: 10.1002/bip.10260
    [Crossref], [PubMed], [CAS], Google Scholar
    28
    Mode of action of membrane active antimicrobial peptides
    Shai, Yechiel
    Biopolymers (2002), 66 (4), 236-248CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
    A review. Water-membrane sol. protein and peptide toxins are used in the defense and offense systems of all organisms, including plants and humans. A major group includes antimicrobial peptides, which serve as a nonspecific defense system that complements the highly specific cell-mediated immune response. The increasing resistance of bacteria to conventional antibiotics stimulated the isolation and characterization of many antimicrobial peptides for potential use as new target antibiotics. The finding of thousands of antimicrobial peptides with variable lengths and sequences, all of which are active at similar concns., suggests a general mechanism for killing bacteria rather than a specific mechanism that requires preferred active structures. Such a mechanism is in agreement with the carpet model that does not require any specific structure or sequence. It seems that when there is an appropriate balance between hydrophobicity and a net pos. charge the peptides are active on bacteria. However, selective activity depends also on other parameters, such as the vol. of the mol., its structure, and its oligomeric state in soln. and membranes. Further, although many studies support that bacterial membrane damage is a lethal event for bacteria, other studies point to a multihit mechanism in which the peptide binds to several targets in the cytoplasmic region of the bacteria.
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  29. 29
    Mojsoska, B.; Jenssen, H. Peptides and peptidomimetics for antimicrobial drug design. Pharmaceuticals 2015, 8, 366– 415,  DOI: 10.3390/ph8030366
    [Crossref], [PubMed], [CAS], Google Scholar
    29
    Peptides and peptidomimetics for antimicrobial drug design
    Mojsoska, Biljana; Jenssen, Haavard
    Pharmaceuticals (2015), 8 (3), 366-415CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)
    The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies. After first dissecting the important physiochem. properties that influence the antimicrobial and toxic properties of antimicrobial peptides, the contributions of individual amino acids with respect to the peptides antibacterial properties are presented. A brief discussion of the mechanisms of action of different antimicrobials as well as the development of bacterial resistance towards antimicrobial peptides follows. Finally, current efforts on novel design strategies and peptidomimetics are introduced to illustrate the importance of antimicrobial peptide research in the development of future antibiotics.
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  30. 30
    Wang, G.; Li, X.; Wang, Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 2016, 44, D1087– D1093,  DOI: 10.1093/nar/gkv1278
    [Crossref], [PubMed], [CAS], Google Scholar
    30
    APD3: the antimicrobial peptide database as a tool for research and education
    Wang, Guangshun; Li, Xia; Wang, Zhe
    Nucleic Acids Research (2016), 44 (D1), D1087-D1093CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    The antimicrobial peptide database (APD, http://aps. unmc.edu/AP/) is an original database initially online in 2003. The APD2 (2009 version) has been regularly updated and further expanded into the APD3. This database currently focuses on natural antimicrobial peptides (AMPs) with defined sequence and activity. It includes a total of 2619 AMPs with 261 bacteriocins from bacteria, 4 AMPs from archaea, 7 from protists, 13 from fungi, 321 from plants and 1972 animal host defense peptides. The APD3 contains 2169 antibacterial, 172 antiviral, 105 anti-HIV, 959 antifungal, 80 antiparasitic and 185 anticancer peptides. Newly annotated are AMPswith antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties. We also describe other searchable annotations, including target pathogens, mol.-binding partners, post-translational modifications and animal models. Amino acid profiles or signatures of natural AMPs are important for peptide classification, prediction and design. Finally, we summarize various database applications in research and education.
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  31. 31
    Lai, Z.; Yuan, X.; Chen, H.; Zhu, Y.; Dong, N.; Shan, A. Strategies employed in the design of antimicrobial peptides with enhanced proteolytic stability. Biotechnol. Adv. 2022, 59, 107962,  DOI: 10.1016/j.biotechadv.2022.107962
    [Crossref], [PubMed], [CAS], Google Scholar
    31
    Strategies employed in the design of antimicrobial peptides with enhanced proteolytic stability
    Lai, Zhenheng; Yuan, Xiaojie; Chen, Hongyu; Zhu, Yunhui; Dong, Na; Shan, Anshan
    Biotechnology Advances (2022), 59 (), 107962CODEN: BIADDD; ISSN:0734-9750. (Elsevier Inc.)
    A review. Due to the alarming developing rate of multidrug-resistant bacterial pathogens, the development and modification of antimicrobial peptides (AMPs) are unprecedentedly active. Despite the fact that considerable efforts have been expended on the discovery and design strategies of AMPs, the clin. translation of peptide antibiotics remains inadequate. A large no. of articles and reviews credited the limited success of AMPs to their poor stability in the biol. environment, particularly their poor proteolytic stability. In the past forty years, various design strategies have been used to improve the proteolytic stability of AMPs, such as sequence modification, cyclization, peptidomimetics, and nanotechnol. Herein, we focus our discussion on the progress made in improving the proteolytic stability of AMPs and the principle, successes, and limitations of various anti-proteolytic design strategies. It is of prospective significance to extend current insights into the degrdn.-related inactivation of AMPs and also alleviate/overcome the problem.
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  32. 32
    Gan, B. H.; Gaynord, J.; Rowe, S. M.; Deingruber, T.; Spring, D. R. The multifaceted nature of antimicrobial peptides: Current synthetic chemistry approaches and future directions. Chem. Soc. Rev. 2021, 50, 7820– 7880,  DOI: 10.1039/d0cs00729c
    [Crossref], [PubMed], [CAS], Google Scholar
    32
    The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions
    Gan, Bee Ha; Gaynord, Josephine; Rowe, Sam M.; Deingruber, Tomas; Spring, David R.
    Chemical Society Reviews (2021), 50 (13), 7820-7880CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Bacterial infections caused by primesuperbugsprime are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clin. potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochem. properties, mechanisms of action, and effects of environmental factors on these features. This review outlines various chem. synthetic strategies that have been applied to develop novel AMPs, including chem. modifications of existing peptides, semi-synthesis, and computer-aided design. We will also highlight novel AMP structures, including hybrids, antimicrobial dendrimers and polypeptides, peptidomimetics, and AMP-drug conjugates and consider recent developments in their chem. synthesis.
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  33. 33
    Büyükkiraz, E. M.; Kesmen, Z. Antimicrobial peptides (AMPs): A promising class of antimicrobial compounds. J. Appl. Microbiol. 2022, 132, 1573– 1596,  DOI: 10.1111/jam.15314
    [Crossref], [PubMed], Google Scholar
    There is no corresponding record for this reference.
  34. 34
    Lei, J.; Sun, L.; Huang, S.; Zhu, C.; Li, P.; He, J.; Mackey, V.; Coy, D. H.; He, Q. The antimicrobial peptides and their potential clinical applications. Am. J. Transl. Res. 2019, 11, 3919– 3931
    [PubMed], [CAS], Google Scholar
    34
    The antimicrobial peptides and their potential clinical applications
    Lei, Jun; Sun, Lichun; Huang, Siyu; Zhu, Chenhong; Li, Ping; He, Jun; Mackey, Vienna; Coy, David H.; He, Quanyong
    American Journal of Translational Research (2019), 11 (7), 3919-3931CODEN: AJTRA7; ISSN:1943-8141. (e-Century Publishing Corp.)
    Nowadays, the bacterial drug resistance leads to serious healthy problem worldwide due to the long-term use and the abuse of traditional antibiotics result in drug resistance of bacteria. Finding a new antibiotic is becoming more and more difficult. Antimicrobial peptides (AMPs) are the host defense peptides with most of them being the cationic (pos. charged) and amphiphilic (hydrophilic and hydrophobic) α-helical peptide mols. The membrane permeability is mostly recognized as the well-accepted mechanism to describe the action of cationic AMPs. These cationic AMPs can bind and interact with the neg. charged bacterial cell membranes, leading to the change of the electrochem. potential on bacterial cell membranes, inducing cell membrane damage and the permeation of larger mols. such as proteins, destroying cell morphol. and membranes and eventually resulting in cell death. These AMPs have been demonstrated to have their own advantages over the traditional antibiotics with a broad-spectrum of antimicrobial activities including anti-bacteria, anti-fungi, anti-viruses, and anti-cancers, and even overcome bacterial drug-resistance. The natural AMPs exist in a variety of organisms and are not stable with a short half-life, more or less toxic side effects, and particularly may have severe hemolytic activity. To open the clin. applications, it is necessary and important to develop the synthetic and long-lasting AMP analogs that overcome the disadvantages of their natural peptides and the potential problems for the drug candidates.
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  35. 35
    Tossi, A.; Scocchi, M.; Skerlavaj, B.; Gennaro, R. Identification and characterization of a primary antibacterial domain in CAP18, a lipopolysaccharide binding protein from rabbit leukocytes. FEBS Lett. 1994, 339, 108– 112,  DOI: 10.1016/0014-5793(94)80395-1
    [Crossref], [PubMed], [CAS], Google Scholar
    35
    Identification and characterization of a primary antibacterial domain in CAP18, a lipopolysaccharide binding protein from rabbit leukocytes
    Tossi, Alessandro; Scocchi, Marco; Skerlavaj, Barbara; Gennaro, Renato
    FEBS Letters (1994), 339 (1-2), 108-12CODEN: FEBLAL; ISSN:0014-5793.
    Secondary structure prediction studies on CAP18, a lipopolysaccharide binding protein from rabbit granulocytes, identified a highly cationic, 21-residue sequence with the tendency to adopt an amphipathic α-helical conformation, as obsd. in many antimicrobial peptides. The corresponding peptide was chem. synthesized and shown to exert a potent bactericidal activity against both Gram-neg. and Gram-pos. bacteria, and a rapid permeabilization of the inner membrane of Escherichia coli. Five analogs were synthesized to elucidate structure/activity relationships. It was found that helix disruption virtually eliminates antibacterial activity, while the degree of amphipathicity and the presence of an arom. residue greatly affect the kinetics of bacterial inner membrane permeabilization.
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  36. 36
    Tencza, S. B.; Creighton, D. J.; Yuan, T.; Vogel, H. J.; Montelaro, R. C.; Mietzner, T. A. Lentivirus-derived antimicrobial peptides: Increased potency by sequence engineering and dimerization. J. Antimicrob. Chemother. 1999, 44, 33– 41,  DOI: 10.1093/jac/44.1.33
    [Crossref], [PubMed], [CAS], Google Scholar
    36
    Lentivirus-derived antimicrobial peptides: increased potency by sequence engineering and dimerization
    Tencza, Sarah Burroughs; Creighton, Donald J.; Yuan, Tao; Vogel, Hans J.; Montelaro, Ronald C.; Mietzner, Timothy A.
    Journal of Antimicrobial Chemotherapy (1999), 44 (1), 33-41CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    We have previously described a family of cationic amphipathic peptides derived from lentivirus envelope proteins that have properties similar to those of naturally occurring antimicrobial peptides. Here, we explored the effects of amino acid truncations and substitutions on the antimicrobial potency and selectivity of the prototype peptide, LLP1. Removal of seven residues from the C-terminus of LLP1 had little effect on potency, but abrogated hemolytic activity. Replacement of the two glutamic acid residues of LLP1 with arginine resulted in a peptide with greater bactericidal activity. We discovered that the cysteine-contg. peptides spontaneously formed disulfide-linked dimers, which were 16-fold more bactericidal to Staphylococcus aureus. Monomeric and dimeric LLP1 possessed similar alpha helical contents, indicating that disulfide formation did not alter the peptide's secondary structure. The dimerization strategy was applied to magainin 2, enhancing its bactericidal activity eight-fold. By optimizing all three properties of LLP1, a highly potent and selective peptide, named TL-1, was produced. This peptide is significantly more potent than LLP1 against Gram-pos. bacteria while maintaining high activity against Gram-neg. organisms and low activity against eukaryotic cells. In addn. to new antimicrobial peptides, these studies contribute useful information on which further peptide engineering efforts can be based.
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  37. 37
    Lau, Y. H.; De Andrade, P.; Wu, Y.; Spring, D. R. Peptide stapling techniques based on different macrocyclisation chemistries. Chem. Soc. Rev. 2015, 44, 91– 102,  DOI: 10.1039/c4cs00246f
    [Crossref], [PubMed], [CAS], Google Scholar
    37
    Peptide stapling techniques based on different macrocyclization chemistries
    Lau, Yu Heng; de Andrade, Peterson; Wu, Yuteng; Spring, David R.
    Chemical Society Reviews (2015), 44 (1), 91-102CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Peptide stapling is a strategy for constraining short peptides typically in an alpha-helical conformation. Stapling is carried out by covalently linking the side-chains of two amino acids, thereby forming a peptide macrocycle. There is an expanding repertoire of stapling techniques based on different macrocyclization chemistries. In this tutorial review, the authors categorize and analyze key examples of peptide stapling in terms of their synthesis and applicability to biol. systems.
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  38. 38
    Migoń, D.; Neubauer, D.; Kamysz, W. Hydrocarbon Stapled Antimicrobial Peptides. Protein J. 2018, 37, 2– 12,  DOI: 10.1007/s10930-018-9755-0
    [Crossref], [PubMed], [CAS], Google Scholar
    38
    Hydrocarbon Stapled Antimicrobial Peptides
    Migon, Dorian; Neubauer, Damian; Kamysz, Wojciech
    Protein Journal (2018), 37 (1), 2-12CODEN: PJROAH; ISSN:1572-3887. (Springer)
    A Review. Antimicrobial peptides are promising candidates for anti-infective pharmaceuticals. Unfortunately, because of their low proteolytic and chem. stability, their usage is generally narrowed down to topical formulations. Until now, numerous approaches to increase peptide stability have been proposed. One of them, peptide hydrocarbon stapling, a modification based on stabilizing peptide secondary structure with a side-chain covalent hydrocarbon bridge, have been successfully applied to many peptides. Moreover, constraining secondary structure of peptides have also been proven to increase their biol. activity. This review article describes studies on hydrocarbon stapled antimicrobial peptides with respect to improved drug-like properties.
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  39. 39
    Blackwell, H. E.; Grubbs, R. H. Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis. Angew. Chem., Int. Ed. 1998, 37, 3281– 3284,  DOI: 10.1002/(sici)1521-3773(19981217)37:23<3281::aid-anie3281>3.0.co;2-v
    [Crossref], [CAS], Google Scholar
    39
    Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis
    Blackwell, Helen E.; Grubbs, Robert H.
    Angewandte Chemie, International Edition (1998), 37 (23), 3281-3284CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
    Ring closing metathesis of acyclic peptide dienes Boc-Val-X-Leu-Aib-Val-X-Leu-OMe [I; Boc = Me3CO2C; X = Ser(CH2CH:CH2), Hse(CH2CH:CH2); Aib = NHCMe2CO], prepd. by std. solid-phase peptide chem., using olefin metathesis catalyst (PCy3)2Cl2Ru:CHPh gave 21- and 23-membered macrocyclic alkenes I in 85 and 90% yields, resp. Hydrogenation of II gave the corresponding alkane-bridged cyclopeptides III in 98% yield. Significant conformational change did not occur on cyclization of I to III, as evidenced by far-UV CD. A crystal structure of III (X = Hse) is reported.
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  40. 40
    Chapuis, H.; Slaninová, J.; Bednárová, L.; Monincová, L.; Buděšínský, M.; Čeřovský, V. Effect of hydrocarbon stapling on the properties of α-helical antimicrobial peptides isolated from the venom of hymenoptera. Amino Acids 2012, 43, 2047– 2058,  DOI: 10.1007/s00726-012-1283-1
    [Crossref], [PubMed], [CAS], Google Scholar
    40
    Effect of hydrocarbon stapling on the properties of α-helical antimicrobial peptides isolated from the venom of hymenoptera
    Chapuis, Hubert; Slaninova, Jirina; Bednarova, Lucie; Monincova, Lenka; Budesinsky, Milos; Cerovsky, Vaclav
    Amino Acids (2012), 43 (5), 2047-2058CODEN: AACIE6; ISSN:0939-4451. (SpringerWienNewYork)
    The impact of inserting hydrocarbon staples into short α-helical antimicrobial peptides lasioglossin III and melectin (antimicrobial peptides of wild bee venom) on their biol. and biophys. properties has been examd. The stapling was achieved by ring-closing olefin metathesis, either between two S-2-(4'-pentenyl) alanine residues (S 5) incorporated at i and i + 4 positions or between R-2-(7'-octenyl) alanine (R 8) and S 5 incorporated at the i and i + 7 positions, resp. We prepd. several lasioglossin III and melectin analogs with a single staple inserted into different positions within the peptide chains as well as analogs with double staples. The stapled peptides exhibited a remarkable increase in hemolytic activity, while their antimicrobial activities decreased. Some single stapled peptides showed a higher resistance against proteolytic degrdn. than native ones, while the double stapled analogs were substantially more resistant. The CD spectra of the singly stapled peptides measured in water showed only a slightly better propensity to form α-helical structure when compared to native peptides, whereas the doubly stapled analogs exhibited dramatically enhanced α-helicity.
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  41. 41
    Bird, G. H.; Madani, N.; Perry, A. F.; Princiotto, A. M.; Supko, J. G.; He, X.; Gavathiotis, E.; Sodroski, J. G.; Walensky, L. D. Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 14093– 14098,  DOI: 10.1073/pnas.1002713107
    [Crossref], [PubMed], [CAS], Google Scholar
    41
    Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic
    Bird, Gregory H.; Madani, Navid; Perry, Alisa F.; Princiotto, Amy M.; Supko, Jeffrey G.; He, Xiaoying; Gavathiotis, Evripidis; Sodroski, Joseph G.; Walensky, Loren D.
    Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (32), 14093-14098, S14093/1-S14093/8CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The pharmacol. utility of lengthy peptides can be hindered by loss of bioactive structure and rapid proteolysis, which limits bioavailability. For example, enfuvirtide (Fuzeon, T20, DP178), a 36-amino acid peptide that inhibits human immunodeficiency virus type 1 (HIV-1) infection by effectively targeting the viral fusion app., has been relegated to a salvage treatment option mostly due to poor in vivo stability and lack of oral bioavailability. To overcome the proteolytic shortcomings of long peptides as therapeutics, the authors examd. the biophys., biol., and pharmacol. impact of inserting all-hydrocarbon staples into an HIV-1 fusion inhibitor. The authors find that peptide double-stapling confers striking protease resistance that translates into markedly improved pharmacokinetic properties, including oral absorption. The authors detd. that the hydrocarbon staples create a proteolytic shield by combining reinforcement of overall α-helical structure, which slows the kinetics of proteolysis, with complete blockade of peptide cleavage at constrained sites in the immediate vicinity of the staple. Importantly, double-stapling also optimizes the antiviral activity of HIV-1 fusion peptides and the antiproteolytic feature extends to other therapeutic peptide templates, such as the diabetes drug exenatide (Byetta). Thus, hydrocarbon double-stapling may unlock the therapeutic potential of natural bioactive polypeptides by transforming them into structurally fortified agents with enhanced bioavailability.
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  42. 42
    Walensky, L. D.; Bird, G. H. Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress. J. Med. Chem. 2014, 57, 6275– 6288,  DOI: 10.1021/jm4011675
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    42
    Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress
    Walensky, Loren D.; Bird, Gregory H.
    Journal of Medicinal Chemistry (2014), 57 (15), 6275-6288CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Protein structure underlies essential biol. processes and provides a blueprint for mol. mimicry that drives drug discovery. Although small mols. represent the lion's share of agents that target proteins for therapeutic benefit, there remains no substitute for the natural properties of proteins and their peptide subunits in the majority of biol. contexts. The peptide α-helix represents a common structural motif that mediates communication between signaling proteins. Because peptides can lose their shape when taken out of context, developing chem. interventions to stabilize their bioactive structure remains an active area of research. The all-hydrocarbon staple has emerged as one such soln., conferring α-helical structure, protease resistance, cellular penetrance, and biol. activity upon successful incorporation of a series of design and application principles. Here, we describe our more than decade-long experience in developing stapled peptides as biomedical research tools and prototype therapeutics, highlighting lessons learned, pitfalls to avoid, and keys to success.
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  43. 43
    Mourtada, R.; Herce, H. D.; Yin, D. J.; Moroco, J. A.; Wales, T. E.; Engen, J. R.; Walensky, L. D. Design of Stapled Antimicrobial Peptides That Overcome Antibiotic Resistance and In Vivo Toxicity. Nat. Biotechnol. 2019, 37, 1186– 1197,  DOI: 10.1038/s41587-019-0222-z
    [Crossref], [PubMed], [CAS], Google Scholar
    43
    Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice
    Mourtada, Rida; Herce, Henry D.; Yin, Daniel J.; Moroco, Jamie A.; Wales, Thomas E.; Engen, John R.; Walensky, Loren D.
    Nature Biotechnology (2019), 37 (10), 1186-1197CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
    The clin. translation of cationic α-helical antimicrobial peptides (AMPs) has been hindered by structural instability, proteolytic degrdn. and in vivo toxicity from nonspecific membrane lysis. Although analyses of hydrophobic content and charge distribution have informed the design of synthetic AMPs with increased potency and reduced in vitro hemolysis, nonspecific membrane toxicity in vivo continues to impede AMP drug development. Here, we analyzed a 58-member library of stapled AMPs (StAMPs) based on magainin II and applied the insights from structure-function-toxicity measurements to devise an algorithm for the design of stable, protease-resistant, potent and nontoxic StAMP prototypes. We show that a lead double-stapled StAMP named Mag(i+4)1,15(A9K,B21A,N22K,S23K) can kill multidrug-resistant Gram-neg. pathogens, such as colistin-resistant Acinetobacter baumannii in a mouse peritonitis-sepsis model, without obsd. hemolysis or renal injury in murine toxicity studies. Inputting the amino acid sequences alone, we further generated membrane-selective StAMPs of pleurocidin, CAP18 and esculentin, highlighting the generalizability of our design platform.
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  44. 44
    Libardo, M. D. J.; Nagella, S.; Lugo, A.; Pierce, S.; Angeles-Boza, A. M. Copper-binding tripeptide motif increases potency of the antimicrobial peptide Anoplin via Reactive Oxygen Species generation. Biochem. Biophys. Res. Commun. 2015, 456, 446– 451,  DOI: 10.1016/j.bbrc.2014.11.104
    [Crossref], [PubMed], [CAS], Google Scholar
    44
    Copper-binding tripeptide motif increases potency of the antimicrobial peptide Anoplin via Reactive Oxygen Species generation
    Libardo, M. Daben J.; Nagella, Sai; Lugo, Andrea; Pierce, Scott; Angeles-Boza, Alfredo M.
    Biochemical and Biophysical Research Communications (2015), 456 (1), 446-451CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
    Antimicrobial peptides (AMPs) are broad spectrum antimicrobial agents that act through diverse mechanisms, this characteristic makes them suitable starting points for development of novel classes of antibiotics. We have previously reported the increase in activity of AMPs upon addn. of the Amino Terminal Copper and Nickel (ATCUN) Binding Unit. Herein we synthesized the membrane active peptide, Anoplin and two ATCUN-Anoplin derivs. and show that the increase in activity is indeed due to the ROS formation by the CuII-ATCUN complex. We found that the ATCUN-Anoplin peptides were up to four times more potent compared to Anoplin alone against std. test bacteria. We studied membrane disruption, and cellular localization and found that addn. of the ATCUN motif did not lead to a difference in these properties. When helical content was calcd., we obsd. that ATCUN-Anoplin had a lower helical compn. We found that ATCUN-Anoplin are able to oxidatively damage lipids in the bacterial membrane and that their activity trails the rate at which ROS is formed by the CuII-ATCUN complexes alone. This study shows that addn. of a metal binding tripeptide motif is a simple strategy to increase potency of AMPs by conferring a secondary action.
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  45. 45
    Zhong, C.; Gou, S.; Liu, T.; Zhu, Y.; Zhu, N.; Liu, H.; Zhang, Y.; Xie, J.; Guo, X.; Ni, J. Study on the effects of different dimerization positions on biological activity of partial d-Amino acid substitution analogues of Anoplin. Microb. Pathog. 2020, 139, 103871,  DOI: 10.1016/j.micpath.2019.103871
    [Crossref], [PubMed], [CAS], Google Scholar
    45
    Study on the effects of different dimerization positions on biological activity of partial D-Amino acid substitution analogues of Anoplin
    Zhong, Chao; Gou, Sanhu; Liu, Tianqi; Zhu, Yuewen; Zhu, Ningyi; Liu, Hui; Zhang, Yun; Xie, Junqiu; Guo, Xiaomin; Ni, Jingman
    Microbial Pathogenesis (2020), 139 (), 103871CODEN: MIPAEV; ISSN:0882-4010. (Elsevier Ltd.)
    Antimicrobial peptides have recently attracted much attention due to their broad-spectrum antimicrobial activity, rapid microbial effects, and minimal tendency toward resistance development. In this study, a series of new C-C terminals and C-N terminals dimer peptides were designed and synthesized by intermol. dimerization of the partial D-amino acid substitution analogs of Anoplin, and the effects of different dimerization positions on biol. activity were researched. The antimicrobial activity and stability of the new C-C terminals and C-N terminals dimer peptides were significantly improved compared with their parent peptide Anoplin. They displayed no obvious hemolytic activity and lower cytotoxicity, with a higher therapeutic index. Furthermore, the new dimer peptides not only enabled to rapidly disrupt bacterial membrane and damage its integrity which was different from conventional antibiotics but also penetrated bacterial membrane into binding to intracellular genomic DNA. More importantly, the new dimer peptides showed excellent antimicrobial activity against multidrug-resistant strains isolated from clinics in contrast to conventional antibiotics with low tendency to develop the bacterial resistance, besides they exhibited better anti-biofilm activity than antibiotic Rifampicin. Interestingly, the C-N terminals dimer peptides were superior to C-C terminals ones in antimicrobial and anti-biofilm activity, therapeutic index, outer membrane permeability, and DNA binding ability, whereas there were no noteworthy effects in different dimerization positions on stability. Thus, these data suggested that dimerization in different positions represented a potent strategy to develop novel antimicrobial agents for fighting against increasing bacterial resistance.
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  46. 46
    Wu, Y.; Lu, D.; Jiang, Y.; Jin, J.; Liu, S.; Chen, L.; Zhang, H.; Zhou, Y.; Chen, H.; Nagle, D. G.; Luan, X.; Zhang, W. Stapled Wasp Venom-Derived Oncolytic Peptides with Side Chains Induce Rapid Membrane Lysis and Prolonged Immune Responses in Melanoma. J. Med. Chem. 2021, 64, 5802– 5815,  DOI: 10.1021/acs.jmedchem.0c02237
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    46
    Stapled Wasp Venom-Derived Oncolytic Peptides with Side Chains Induce Rapid Membrane Lysis and Prolonged Immune Responses in Melanoma
    Wu, Ye; Lu, Dong; Jiang, Yixin; Jin, Jinmei; Liu, Sanhong; Chen, Lili; Zhang, Hong; Zhou, Yudong; Chen, Hongzhuan; Nagle, Dale G.; Luan, Xin; Zhang, Weidong
    Journal of Medicinal Chemistry (2021), 64 (9), 5802-5815CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Peptide stapling chem. represents an attractive strategy to promote the clin. translation of protein epitope mimetics, but its use has not been applied to natural cytotoxic peptides (NCPs) to produce new oncolytic peptides. Based on a wasp venom peptide, a series of stapled anoplin peptides (StAnos) were prepd. The optimized stapled Ano-3/3s were shown to be protease-resistant and exerted superior tumor cell-selective cytotoxicity by rapid membrane disruption. In addn., Ano-3/3s induced tumor ablation in mice through the direct oncolytic effect and subsequent stimulation of immunogenic cell death. This synergistic oncolytic-immunotherapy effect is more remarkable on melanoma than on triple-neg. breast cancer in vivo. The efficacies exerted by Ano-3/3s on melanoma were further characterized by CD8+ T cell infiltration, and the addn. of anti-CD8 antibodies diminished the long-term antitumor effects. In summary, these results support stapled peptide chem. as an advantageous method to enhance the NCP potency for oncolytic therapy.
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  47. 47
    Wang, Y.; Chen, J.; Zheng, X.; Yang, X.; Ma, P.; Cai, Y.; Zhang, B.; Chen, Y. Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity. J. Pept. Sci. 2014, 20, 945– 951,  DOI: 10.1002/psc.2705
    [Crossref], [PubMed], [CAS], Google Scholar
    47
    Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity
    Wang, Yang; Chen, Jianbo; Zheng, Xin; Yang, Xiaoli; Ma, Panpan; Cai, Ying; Zhang, Bangzhi; Chen, Yuan
    Journal of Peptide Science (2014), 20 (12), 945-951CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
    Currently, novel antibiotics are urgently required to combat the emergence of drug-resistant bacteria. Antimicrobial peptides with membrane-lytic mechanism of action have attracted considerable interest. Anoplin, a natural α-helical amphiphilic antimicrobial peptide, is an ideal research template because of its short sequence. In this study, we designed and synthesized a group of analogs of anoplin. Among these analogs, anoplin-4 composed of D-amino acids displayed the highest antimicrobial activity due to increased charge, hydrophobicity, and amphiphilicity. Gratifyingly, anoplin-4 showed low toxicity to host cells, indicating high bacterial selectivity. Furthermore, the mortality rate of mice infected with Escherichia coli was significantly reduced by anoplin-4 treatment relative to anoplin. In conclusion, anoplin-4 is a novel anoplin analog with high antimicrobial activity and enzymic stability, which may represent a potent agent for the treatment of infection. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.
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  48. 48
    Wojciechowska, M.; Miszkiewicz, J.; Trylska, J. Conformational Changes of Anoplin, W-MreB1–9, and (KFF)3K Peptides near the Membranes. Int. J. Mol. Sci. 2020, 21, 9672,  DOI: 10.3390/ijms21249672
    [Crossref], [PubMed], [CAS], Google Scholar
    48
    Conformational changes of anoplin, W-MreB1-9, and (KFF)3K peptides near the membranes
    Wojciechowska, Monika; Miszkiewicz, Joanna; Trylska, Joanna
    International Journal of Molecular Sciences (2020), 21 (24), 9672CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    Many peptides interact with biol. membranes, but elucidating these interactions is challenging because cellular membranes are complex and peptides are structurally flexible. To contribute to understanding how the membrane-active peptides behave near the membranes, we investigated peptide structural changes in different lipid surroundings. We focused on two antimicrobial peptides, anoplin and W-MreB1-9, and one cell-penetrating peptide, (KFF)3K. Firstly, by using CD spectroscopy, we detd. the secondary structures of these peptides when interacting with micelles, liposomes, E. coli lipopolysaccharides, and live E. coli bacteria. The peptides were disordered in the buffer, but anoplin and W-MreB1-9 displayed lipid-induced helicity. Yet, structural changes of the peptide depended on the compn. and concn. of the membranes. Secondly, we quantified the destructive activity of peptides against liposomes by monitoring the release of a fluorescent dye (calcein) from the liposomes treated with peptides. We obsd. that only for anoplin and W-MreB1-9 calcein leakage from liposomes depended on the peptide concn. Thirdly, bacterial growth inhibition assays showed that peptide conformational changes, evoked by the lipid environments, do not directly correlate with the antimicrobial activity of the peptides. However, understanding the relation between peptide structural properties, mechanisms of membrane disruption, and their biol. activities can guide the design of membrane-active peptides.
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  49. 49
    Wojciechowska, M.; Macyszyn, J.; Miszkiewicz, J.; Grzela, R.; Trylska, J. Stapled Anoplin as an Antibacterial Agent. Front. Microbiol. 2021, 12, 772038,  DOI: 10.3389/fmicb.2021.772038
    [Crossref], [PubMed], [CAS], Google Scholar
    49
    Stapled Anoplin as an Antibacterial Agent
    Wojciechowska Monika; Macyszyn Julia; Miszkiewicz Joanna; Grzela Renata; Trylska Joanna; Miszkiewicz Joanna; Grzela Renata
    Frontiers in microbiology (2021), 12 (), 772038 ISSN:1664-302X.
    Anoplin is a linear 10-amino acid amphipathic peptide (Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-NH2 ) derived from the venom sac of the solitary wasp. It has broad antimicrobial activity, including an antibacterial one. However, the inhibition of bacterial growth requires several dozen micromolar concentrations of this peptide. Anoplin is positively charged and directly interacts with anionic biological membranes forming an α-helix that disrupts the lipid bilayer. To improve the bactericidal properties of anoplin by stabilizing its helical structure, we designed and synthesized its analogs with hydrocarbon staples. The staple was introduced at two locations resulting in different charges and amphipathicity of the analogs. Circular dichroism studies showed that all modified anoplins adopted an α-helical conformation, both in the buffer and in the presence of membrane mimics. As the helicity of the stapled anoplins increased, their stability in trypsin solution improved. Using the propidium iodide uptake assay in Escherichia coli and Staphylococcus aureus, we confirmed the bacterial membrane disruption by the stapled anoplins. Next, we tested the antimicrobial activity of peptides on a range of Gram-negative and Gram-positive bacteria. Finally, we evaluated peptide hemolytic activity on sheep erythrocytes and cytotoxicity on human embryonic kidney 293 cells. All analogs showed higher antimicrobial activity than unmodified anoplin. Depending on the position of the staple, the peptides were more effective either against Gram-negative or Gram-positive bacteria. Anoplin[5-9], with a lower positive charge and increased hydrophobicity, had higher activity against Gram-positive bacteria but also showed hemolytic and destructive effects on eukaryotic cells. Contrary, anoplin[2-6] with a similar charge and amphipathicity as natural anoplin effectively killed Gram-negative bacteria, also pathogenic drug-resistant strains, without being hemolytic and toxic to eukaryotic cells. Our results showed that anoplin charge, amphipathicity, and location of hydrophobic residues affect the peptide destructive activity on the cell wall, and thus, its antibacterial activity. This means that by manipulating the charge and position of the staple in the sequence, one can manipulate the antimicrobial activity.
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  50. 50
    Sahariah, P.; Sørensen, K. K.; Hjálmarsdóttir, M. A.; Sigurjónsson, Ó. E.; Jensen, K. J.; Másson, M.; Thygesen, M. B. Antimicrobial peptide shows enhanced activity and reduced toxicity upon grafting to chitosan polymers. Chem. Commun. 2015, 51, 11611– 11614,  DOI: 10.1039/c5cc04010h
    [Crossref], [PubMed], [CAS], Google Scholar
    50
    Antimicrobial peptide shows enhanced activity and reduced toxicity upon grafting to chitosan polymers
    Sahariah, Priyanka; Soerensen, Kasper K.; Hjalmarsdottir, Martha A.; Sigurjonsson, Olafur E.; Jensen, Knud J.; Masson, Mar; Thygesen, Mikkel B.
    Chemical Communications (Cambridge, United Kingdom) (2015), 51 (58), 11611-11614CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Here we report that grafting of a short antimicrobial peptide, anoplin, to chitosan polymers is a strategy for abolishing the hemolytic propensity, and at the same time increasing the activity of the parent peptide. Anoplin-chitosan conjugates were synthesized by CuAAC reaction of multiple peptides through 2-azidoacetyl groups on chitosan.
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  51. 51
    Konno, K.; Hisada, M.; Fontana, R.; Lorenzi, C. C. B.; Naoki, H.; Itagaki, Y.; Miwa, A.; Kawai, N.; Nakata, Y.; Yasuhara, T.; Ruggiero Neto, J.; de Azevedo, W. F.; Palma, M. S.; Nakajima, T. Anoplin, a novel antimicrobial peptide from the venom of the solitary wasp Anoplius samariensis. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 2001, 1550, 70– 80,  DOI: 10.1016/s0167-4838(01)00271-0
    [Crossref], [PubMed], [CAS], Google Scholar
    51
    Anoplin, a novel antimicrobial peptide from the venom of the solitary wasp Anoplius samariensis
    Konno, Katsuhiro; Hisada, Miki; Fontana, Renato; Lorenzi, Carla C. B.; Naoki, Hideo; Itagaki, Yasuhiro; Miwa, Akiko; Kawai, Nobufumi; Nakata, Yoshihiro; Yasuhara, Tadashi; Ruggiero Neto, Joao; de Azevedo, Walter F.; Palma, Mario S.; Nakajima, Terumi
    Biochimica et Biophysica Acta, Protein Structure and Molecular Enzymology (2001), 1550 (1), 70-80CODEN: BBAEDZ; ISSN:0167-4838. (Elsevier B.V.)
    A novel antimicrobial peptide, anoplin, was purified from the venom of the solitary wasp Anoplius samariensis. The sequence was mostly analyzed by mass spectrometry, which was corroborated by solid-phase synthesis. Anoplin, composed of 10 amino acid residues, Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-NH2, has a high homol. to crabrolin and mastoparan-X, the mast cell degranulating peptides from social wasp venoms, and, therefore, can be predicted to adopt an amphipathic α-helix secondary structure. In fact, the CD spectra of anoplin in the presence of trifluoroethanol or SDS showed a high content, up to 55%, of the α-helical conformation. A modeling study of anoplin based on its homol. to mastoparan-X supported the CD results. Biol. evaluation using the synthetic peptide revealed that this peptide exhibited potent activity in stimulating degranulation from rat peritoneal mast cells and broad-spectrum antimicrobial activity against both Gram-pos. and Gram-neg. bacteria. Therefore, this is the first antimicrobial component to be found in the solitary wasp venom and it may play a key role in preventing potential infection by microorganisms during prey consumption by their larvae. Moreover, this peptide is the smallest among the linear α-helical antimicrobial peptides hitherto found in nature, which is advantageous for chem. manipulation and medical application.
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  52. 52
    Klahn, P.; Brönstrup, M. Bifunctional antimicrobial conjugates and hybrid antimicrobials. Nat. Prod. Rep. 2017, 34, 832– 885,  DOI: 10.1039/c7np00006e
    [Crossref], [PubMed], [CAS], Google Scholar
    52
    Bifunctional antimicrobial conjugates and hybrid antimicrobials
    Klahn, P.; Broenstrup, M.
    Natural Product Reports (2017), 34 (7), 832-885CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
    A review. Novel antimicrobial drugs are continuously needed to counteract bacterial resistance development. An innovative mol. design strategy for novel antibiotic drugs is based on the hybridization of an antibiotic with a second functional entity. Such conjugates can be grouped into two major categories. In the first category (antimicrobial hybrids), both functional elements of the hybrid exert antimicrobial activity. Due to the dual targeting, resistance development can be significantly impaired, the pharmacokinetic properties can be superior compared to combination therapies with the single antibiotics, and the antibacterial potency is often enhanced in a synergistic manner. In the second category (antimicrobial conjugates), one functional moiety controls the accumulation of the other part of the conjugate, e.g. by mediating an active transport into the bacterial cell or blocking the efflux. This approach is mostly applied to translocate compds. across the cell envelope of Gram-neg. bacteria through membrane-embedded transporters (e.g. siderophore transporters) that provide nutrition and signalling compds. to the cell. Such 'Trojan Horse' approaches can expand the antibacterial activity of compds. against Gram-neg. pathogens, or offer new options for natural products that could not be developed as standalone antibiotics, e.g. due to their toxicity.
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  53. 53
    Deshayes, S.; Xian, W.; Schmidt, N. W.; Kordbacheh, S.; Lieng, J.; Wang, J.; Zarmer, S.; Germain, S. S.; Voyen, L.; Thulin, J.; Wong, G. C. L.; Kasko, A. M. Designing Hybrid Antibiotic Peptide Conjugates to Cross Bacterial Membranes. Bioconjugate Chem. 2017, 28, 793– 804,  DOI: 10.1021/acs.bioconjchem.6b00725
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    53
    Designing Hybrid Antibiotic Peptide Conjugates To Cross Bacterial Membranes
    Deshayes, Stephanie; Xian, Wujing; Schmidt, Nathan W.; Kordbacheh, Shadi; Lieng, Juelline; Wang, Jennifer; Zarmer, Sandra; Germain, Samantha St.; Voyen, Laura; Thulin, Julia; Wong, Gerard C. L.; Kasko, Andrea M.
    Bioconjugate Chemistry (2017), 28 (3), 793-804CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    We design hybrid antibiotic peptide conjugates that can permeate membranes. Integration of multiple components with different functions into a single mol. is often problematic, due to competing chem. requirements for different functions and to mutual interference. By examg. the structure of antimicrobial peptides, we show that it is possible to design and synthesize membrane active antibiotic peptide conjugates that synergistically combine multiple forms of antimicrobial activity, resulting in unusually strong activity against persistent bacterial strains.
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  54. 54
    Fosso, M. Y.; Li, Y.; Garneau-Tsodikova, S. New trends in the use of aminoglycosides. MedChemComm 2014, 5, 1075– 1091,  DOI: 10.1039/c4md00163j
    [Crossref], [PubMed], [CAS], Google Scholar
    54
    New trends in the use of aminoglycosides
    Fosso, Marina Y.; Li, Yijia; Garneau-Tsodikova, Sylvie
    MedChemComm (2014), 5 (8), 1075-1091CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    A review. Despite their inherent toxicity and the acquired bacterial resistance that continuously threaten their long-term clin. use, aminoglycosides (AGs) still remain valuable components of the antibiotic armamentarium. Recent literature shows that the AGs' role has been further expanded as multi-tasking players in different areas of study. This review aims at presenting some of the new trends obsd. in the use of AGs in the past decade, along with the current understanding of their mechanisms of action in various bacterial and eukaryotic cellular processes.
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  55. 55
    Chandrika, N. T.; Garneau-Tsodikova, S. A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides. MedChemComm 2016, 7, 50– 68,  DOI: 10.1039/c5md00453e
    [Crossref], [PubMed], [CAS], Google Scholar
    55
    A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides
    Chandrika, Nishad Thamban; Garneau-Tsodikova, Sylvie
    MedChemComm (2016), 7 (1), 50-68CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-neg. and Gram-pos. bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) assocd. with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concn. by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011-2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.
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  56. 56
    Bera, S.; Zhanel, G. G.; Schweizer, F. Antibacterial activities of aminoglycoside antibiotics-derived cationic amphiphiles. Polyol-modified neomycin B-Kanamycin A-Amikacin-and Neamine-based amphiphiles with potent broad spectrum antibacterial activity. J. Med. Chem. 2010, 53, 3626– 3631,  DOI: 10.1021/jm1000437
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    56
    Antibacterial activities of aminoglycoside antibiotic-derived cationic amphiphiles: Polyol-modified neomycin B-, kanamycin A-, amikacin-, and neamine-based amphiphiles with potent broad spectrum antibacterial activity
    Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
    Journal of Medicinal Chemistry (2010), 53 (9), 3626-3631CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Cationic amphiphiles contg. multiple pos. charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. The authors have prepd. a novel class of cationic amphiphiles termed aminoglycoside antibiotics-derived amphiphiles in which the polyol scaffold of the aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. The results show that the nature of the polyol modification as well as the nature of the aminoglycoside antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles contg. unsubstituted arom. rings. These analogs exhibit up to 256-fold enhanced antibacterial activity against resistant strains when compared to neomycin B while retaining most of their activity against neomycin B-susceptible strains.
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  57. 57
    Neumann, W.; Nolan, E. M. Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics. J. Biol. Inorg. Chem. 2018, 23, 1025– 1036,  DOI: 10.1007/s00775-018-1588-y
    [Crossref], [PubMed], [CAS], Google Scholar
    57
    Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics
    Neumann, Wilma; Nolan, Elizabeth M.
    JBIC, Journal of Biological Inorganic Chemistry (2018), 23 (7), 1025-1036CODEN: JJBCFA; ISSN:0949-8257. (Springer)
    Abstr.: Bacterial iron uptake machinery can be hijacked for the targeted delivery of antibiotics into pathogens by attaching antibiotics to siderophores, iron chelators that are employed by bacteria to obtain this essential nutrient. We synthesized and evaluated Ent-SS-Cipro, a siderophore-antibiotic conjugate comprised of the triscatecholate siderophore enterobactin and the fluoroquinolone antibiotic ciprofloxacin that contains a self-immolative disulfide linker. This linker is designed to be cleaved after uptake into the reducing environment of the bacterial cytoplasm. We show that the disulfide bond of Ent-SS-Cipro is cleaved by reducing agents, including the cellular reductant glutathione, which results in release of the unmodified fluoroquinolone antibiotic. Antibacterial activity assays against a panel of Escherichia coli show that Ent-SS-Cipro exhibits activity against some, but not all, E. coli. This work informs the design of siderophore-antibiotic conjugates, particularly those carrying antibiotics with cytoplasmic targets that require release after uptake into bacterial cells, and indicates that disulfide linkers may not be generally applicable for conjugation strategies of antibiotics.
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  58. 58
    Wierzba, A.; Wojciechowska, M.; Trylska, J.; Gryko, D. Vitamin B12 Suitably Tailored for Disulfide-Based Conjugation. Bioconjugate Chem. 2016, 27, 189– 197,  DOI: 10.1021/acs.bioconjchem.5b00599
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    58
    Vitamin B12 Suitably Tailored for Disulfide-Based Conjugation
    Wierzba, Aleksandra; Wojciechowska, Monika; Trylska, Joanna; Gryko, Dorota
    Bioconjugate Chemistry (2016), 27 (1), 189-197CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Vitamin B12 has been proposed to be a natural vector for the in vivo delivery of biol. active compds. Most synthetic methodologies leading to vitamin B12 conjugates involve functionalization at the 5' position via either carbamate-based linkages or using copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC), resulting in stable conjugates that are not cleaved within the cell. We have developed a novel vitamin B12 deriv. suitably tailored for disulfide-based conjugation that can undergo cleavage in the presence of glutathione, the most abundant thiol in mammalian cells. This active compd. is simple to prep. and allows for the direct disulfide-based attachment of therapeutic cargos.
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  59. 59
    Równicki, M.; Wojciechowska, M.; Wierzba, A. J.; Czarnecki, J.; Bartosik, D.; Gryko, D.; Trylska, J. Vitamin B12 as a carrier of peptide nucleic acid (PNA) into bacterial cells. Sci. Rep. 2017, 7, 7644– 7711,  DOI: 10.1038/s41598-017-08032-8
    [Crossref], [PubMed], [CAS], Google Scholar
    59
    Vitamin B12 as a carrier of peptide nucleic acid (PNA) into bacterial cells
    Rownicki Marcin; Rownicki Marcin; Wojciechowska Monika; Trylska Joanna; Wierzba Aleksandra J; Gryko Dorota; Czarnecki Jakub; Bartosik Dariusz
    Scientific reports (2017), 7 (1), 7644 ISSN:.
    Short modified oligonucleotides targeted at bacterial DNA or RNA could serve as antibacterial agents provided that they are efficiently taken up by bacterial cells. However, the uptake of such oligonucleotides is hindered by the bacterial cell wall. To overcome this problem, oligomers have been attached to cell-penetrating peptides, but the efficiency of delivery remains poor. Thus, we have investigated the ability of vitamin B12 to transport peptide nucleic acid (PNA) oligomers into cells of Escherichia coli and Salmonella Typhimurium. Vitamin B12 was covalently linked to a PNA oligomer targeted at the mRNA of a reporter gene expressing Red Fluorescent Protein. Cu-catalyzed 1,3-dipolar cycloaddition was employed for the synthesis of PNA-vitamin B12 conjugates; namely the vitamin B12 azide was reacted with PNA possessing the terminal alkyne group. Different types of linkers and spacers between vitamin B12 and PNA were tested, including a disulfide bond. We found that vitamin B12 transports antisense PNA into E. coli cells more efficiently than the most widely used cell-penetrating peptide (KFF)3K. We also determined that the structure of the linker impacts the antisense effect. The results of this study provide the foundation for developing vitamin B12 as a carrier of PNA oligonucleotides into bacterial cells.
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  60. 60
    Gautier, R.; Douguet, D.; Antonny, B.; Drin, G. HELIQUEST: A web server to screen sequences with specific α-helical properties. Bioinformatics 2008, 24, 2101– 2102,  DOI: 10.1093/bioinformatics/btn392
    [Crossref], [PubMed], [CAS], Google Scholar
    60
    HELIQUEST: a web server to screen sequences with specific α-helical properties
    Gautier, Romain; Douguet, Dominique; Antonny, Bruno; Drin, Guillaume
    Bioinformatics (2008), 24 (18), 2101-2102CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
    Summary: HELIQUEST calcs. the physicochem. properties and amino acid compn. of an α-helix and screens databases to identify protein segments possessing similar features. This server is also dedicated to mutating helixes manually or automatically by genetic algorithm to design analogs of defined features. Availability: http://heliquest.ipmc.cnrs.fr.
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  61. 61
    Hull, R.; Klinger, J. D.; Moody, E. E. M. Isolation and characterization of mutants of Escherichia coli K12 resistant to the new aminoglycoside antibiotic, amikacin. J. Gen. Microbiol. 1976, 94, 389– 394,  DOI: 10.1099/00221287-94-2-389
    [Crossref], [PubMed], [CAS], Google Scholar
    61
    Isolation and characterization of mutants of Escherichia coli K12 resistant to the new aminoglycoside antibiotic, amikacin
    Hull, R.; Klinger, J. D.; Moody, E. E. M.
    Journal of General Microbiology (1976), 94 (2), 389-94CODEN: JGMIAN; ISSN:0022-1287.
    Spontaneous mutants of Escherichia coli K12 were resistant to amikacin and simultaneously acquired cross-resistance to kanamycin, gentamicin, and neomycin, but not to streptomycin or spectinomycin. The sensitivity of the mutants to ampicillin, tetracycline, and polymyxin was not affected. The genetic locus for ribosomal resistance to amikacin was linked to the strA gene and was located distal to spcA with respect to aroE.
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  62. 62
    Jiang, L.; Watkins, D.; Jin, Y.; Gong, C.; King, A.; Washington, A. Z.; Green, K. D.; Garneau-Tsodikova, S.; Oyelere, A. K.; Arya, D. P. Rapid synthesis, RNA binding, and antibacterial screening of a peptidic-aminosugar (PA) library. ACS Chem. Biol. 2015, 10, 1278– 1289,  DOI: 10.1021/cb5010367
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    62
    Rapid Synthesis, RNA Binding, and Antibacterial Screening of a Peptidic-Aminosugar (PA) Library
    Jiang, Liuwei; Watkins, Derrick; Jin, Yi; Gong, Changjun; King, Ada; Washington, Arren Z.; Green, Keith D.; Garneau-Tsodikova, Sylvie; Oyelere, Adegboyega K.; Arya, Dev P.
    ACS Chemical Biology (2015), 10 (5), 1278-1289CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    A 215-member mono- and diamino acid peptidic-aminosugar (PA) library, with neomycin as the model aminosugar, was systematically and rapidly synthesized via solid-phase synthesis. Antibacterial activities of the PA library, on 13 bacterial strains (seven Gram-pos. and six Gram-neg. bacterial strains), and binding affinities of the PA library for a 27-base model of the bacterial 16S ribosomal A-site RNA were evaluated using high-throughput screening. The results of the two assays were correlated using Ribosomal Binding-Bacterial Inhibition Plot (RB-BIP) anal. to provide structure-activity relationship (SAR) information. In this work, the authors have identified PAs that can discriminate the E. coli A-site from the human A-site by up to a 28-fold difference in binding affinity. Aminoglycoside-modifying enzyme activity studies indicate that APH(2'')-Ia showed nearly complete removal of activity with a no. of PAs. The synthesis of the compd. library and screening can both be performed rapidly, allowing for an iterative process of aminoglycoside synthesis and screening of PA libraries for optimal binding and antibacterial activity for lead identification.
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  63. 63
    Fair, R. J.; Hensler, M. E.; Thienphrapa, W.; Dam, Q. N.; Nizet, V.; Tor, Y. Selectively Guanidinylated Aminoglycosides as Antibiotics. ChemMedChem 2012, 7, 1237– 1244,  DOI: 10.1002/cmdc.201200150
    [Crossref], [PubMed], [CAS], Google Scholar
    63
    Selectively guanidinylated aminoglycosides as antibiotics
    Fair, Richard J.; Hensler, Mary E.; Thienphrapa, Wdee; Dam, Quang N.; Nizet, Victor; Tor, Yitzhak
    ChemMedChem (2012), 7 (7), 1237-1244, S1237/1-S1237/26CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The emergence of virulent, drug-resistant bacterial strains coupled with a minimal output of new pharmaceutical agents to combat them makes this a crit. time for antibacterial research. Aminoglycosides are a well studied, highly potent class of naturally occurring antibiotics with scaffolds amenable to modification, and therefore, they provide an excellent starting point for the development of semisynthetic, next-generation compds. To explore the potential of this approach, the authors synthesized a small library of aminoglycoside derivs. selectively and minimally modified at one or two positions with a guanidine group replacing the corresponding amine or hydroxy functionality. Most guanidino-aminoglycosides showed increased affinity for the ribosomal decoding rRNA site, the cognate biol. target of the natural products, when compared with their parent antibiotics, as measured by an in vitro fluorescence resonance energy transfer (FRET) A-site binding assay. Addnl., certain analogs showed improved min. inhibitory concn. (MIC) values against resistant bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An amikacin deriv. holds particular promise with activity greater than or equal to the parent antibiotic in the majority of bacterial strains tested.
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  64. 64
    Spears, R. J.; McMahon, C.; Chudasama, V. Cysteine protecting groups: Applications in peptide and protein science. Chem. Soc. Rev. 2021, 50, 11098– 11155,  DOI: 10.1039/d1cs00271f
    [Crossref], [PubMed], [CAS], Google Scholar
    64
    Cysteine protecting groups: applications in peptide and protein science
    Spears, Richard J.; McMahon, Cliona; Chudasama, Vijay
    Chemical Society Reviews (2021), 50 (19), 11098-11155CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Protecting group chem. for the cysteine thiol group has enabled a vast array of peptide and protein chem. over the last several decades. Increasingly sophisticated strategies for the protection, and subsequent deprotection, of cysteine have been developed, facilitating synthesis of complex disulfide-rich peptides, semisynthesis of proteins, and peptide/protein labeling in vitro and in vivo. In this review, we analyze and discuss the 60+ individual protecting groups reported for cysteine, highlighting their applications in peptide synthesis and protein science.
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  65. 65
    Westermann, B.; Dörner, S.; Brauch, S.; Schaks, A.; Heinke, R.; Stark, S.; Van Delft, F. L.; Van Berkel, S. S. CuAAC-mediated diversification of aminoglycoside-arginine conjugate mimics by non-reducing di- and trisaccharides. Carbohydr. Res. 2013, 371, 61– 67,  DOI: 10.1016/j.carres.2013.02.003
    [Crossref], [PubMed], [CAS], Google Scholar
    65
    CuAAC-mediated diversification of aminoglycoside-arginine conjugate mimics by non-reducing disaccharide and trisaccharides
    Westermann, Bernhard; Doerner, Simon; Brauch, Sebastian; Schaks, Angela; Heinke, Ramona; Stark, Sebastian; van Delft, Floris L.; van Berkel, Sander S.
    Carbohydrate Research (2013), 371 (), 61-67CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
    Di- and triguanidinylation of trehalose, sucrose, and melizitose has been achieved via a Huisgen-cycloaddn. approach. They can serve as aminoglycoside-arginine conjugate mimics, which has been demonstrated by their biol. profiles in assays against Bacillus subtilis. For comparative studies, tetra-guanidinylated neamine and kanamycin derivs. have also been synthesized and evaluated.
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  66. 66
    Kobayashi, K.; Taguchi, A.; Cui, Y.; Shida, H.; Muguruma, K.; Takayama, K.; Taniguchi, A.; Hayashi, Y. “On-Resin” Disulfide Peptide Synthesis with Methyl 3-Nitro-2-pyridinesulfenate. Eur. J. Org. Chem. 2021, 2021, 956– 963,  DOI: 10.1002/ejoc.202001517
    [Crossref], [CAS], Google Scholar
    66
    "On-resin" disulfide peptide synthesis with methyl 3-nitro-2-pyridinesulfenate
    Kobayashi, Kiyotaka; Taguchi, Akihiro; Cui, Yan; Shida, Hayate; Muguruma, Kyohei; Takayama, Kentaro; Taniguchi, Atsuhiko; Hayashi, Yoshio
    European Journal of Organic Chemistry (2021), 2021 (6), 956-963CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    New methodologies for the construction of full peptide structures with all disulfide bonds on the resin are attractive for the development of solid phase peptide synthesis. Detailed reaction conditions for the on-resin disulfide bond formation have been investigated using a mild and chem. stable oxidizing reagent, Me 3-nitro-2-pyridinesulfenate (Npys-OMe). Monocyclic oxytocin, MCH and bicyclic α-conotoxin ImI were synthesized in both semi-automated and full-automated protocols. It was found that on-resin intramol. disulfide bond formation with Npys-OMe proceeds with the minimal formation of peptide oligomers by adopting a solvent system with 0.4 M LiCl/DMF. Crude peptides with complete disulfide bond patterns can be obtained in high purity using both protocols. This minimized the RP-HPLC purifn. step and the desired peptides were obtained with better yields. To our knowledge, this is the first fully automated construction of a bicyclic disulfide peptide on resin with more than 50% purity in Fmoc-based SPPS. These results suggest that Npys-OMe is a useful reagent for the disulfide bond formation in automated protocols.
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  67. 67
    Galande, A. K.; Weissleder, R.; Tung, C. H. An effective method of on-resin disulfide bond formation in peptides. J. Comb. Chem. 2005, 7, 174– 177,  DOI: 10.1021/cc049839r
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    67
    An Effective Method of On-Resin Disulfide Bond Formation in Peptides
    Galande, Amit K.; Weissleder, Ralph; Tung, Ching-Hsuan
    Journal of Combinatorial Chemistry (2005), 7 (2), 174-177CODEN: JCCHFF; ISSN:1520-4766. (American Chemical Society)
    Five disulfide-bridged peptides were synthesized on solid phase. The peptides were assembled using std. Fmoc chem. on Wang resin with tert-butylthio (S-t-Bu) and 4-methoxytrityl (Mmt) as thiol-protecting groups for cysteines undergoing disulfide bond formation. In the first step, S-t-Bu was removed by redn. to liberate free thiol by treating the resin with 20% mercaptoethanol in DMF for 3 h. The resin was then reacted with a 10-fold excess of 2,2'-dithiobis(5-nitropyridine) (DTNB) in CH2Cl2 for 1 h, and the free thiol was thus reprotected and activated with the 5-nitropyridinesulfenyl (5-Npys) group. This was followed by the cyclization step in which the resin was treated with 1% TFA in CH2Cl2 in the the presence of triisopropylsilane (TIS) as the scavenger. The reaction was monitored by measuring the absorbance of 5-nitropyridine-2-thione at 386 nm; all cyclizations were completed in <20 min.
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  68. 68
    Postma, T. M.; Albericio, F. N-Chlorosuccinimide, an efficient reagent for on-resin disulfide formation in solid-phase peptide synthesis. Org. Lett. 2013, 15, 616– 619,  DOI: 10.1021/ol303428d
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    68
    N-Chlorosuccinimide, an Efficient Reagent for On-Resin Disulfide Formation in Solid-Phase Peptide Synthesis
    Postma, Tobias M.; Albericio, Fernando
    Organic Letters (2013), 15 (3), 616-619CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    N-Chlorosuccinimide is described as a widely applicable on-resin disulfide-forming reagent. Disulfide bond formation was completed within 15 min in DMF. This strategy was successfully used in the synthesis of oxytocin and a regioselective synthesis of an α-conotoxin. Moreover, disulfide formation with N-chlorosuccinimide was found to be compatible with oxidn.-prone methionine and tryptophan.
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  69. 69
    Altinbasak, I.; Arslan, M.; Sanyal, R.; Sanyal, A. Pyridyl disulfide-based thiol-disulfide exchange reaction: Shaping the design of redox-responsive polymeric materials. Polym. Chem. 2020, 11, 7603– 7624,  DOI: 10.1039/d0py01215g
    [Crossref], [CAS], Google Scholar
    69
    Pyridyl disulfide-based thiol-disulfide exchange reaction: shaping the design of redox-responsive polymeric materials
    Altinbasak, Ismail; Arslan, Mehmet; Sanyal, Rana; Sanyal, Amitav
    Polymer Chemistry (2020), 11 (48), 7603-7624CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    A review. Recent years have witnessed an increase in the utilization of stimuli-responsive polymers in various areas of materials and biol. sciences. In particular, disulfide linkage contg. redox-responsive polymers have attracted interest in various biomedical applications ranging from fabrication of drug delivery vehicles to diagnostic interfaces. Cleavage of the disulfide linkage in the presence of an endogenous reducing agent, namely, glutathione, also found in increased amts. in diseased tissues has led to the incorporation of this particular linkage into several therapeutic platforms. Among the various methods available for introducing the redox-sensitive disulfide unit, the pyridyl disulfide (PDS) moiety has been one of the most widely employed building blocks. The rapid thiol-disulfide exchange reaction of the PDS group with thiol functional groups has been exploited from the reversible conjugation of therapeutic agents to the fabrication of redox-responsive crosslinked materials such as hydrogels and nanogels. This review provides an overview of various synthetic approaches utilized to incorporate this particular thiol-reactive motif into different types of polymeric materials and briefly highlights its utilization to obtain functional materials.
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  70. 70
    Lee, J. Y.; Yang, S. T.; Lee, S. K.; Jung, H. H.; Shin, S. Y.; Hahm, K. S.; Kim, J. I. Salt-resistant homodimeric bactenecin, a cathelicidin-derived antimicrobial peptide. FEBS J. 2008, 275, 3911– 3920,  DOI: 10.1111/j.1742-4658.2008.06536.x
    [Crossref], [PubMed], [CAS], Google Scholar
    70
    Salt-resistant homodimeric bactenecin, a cathelicidin-derived antimicrobial peptide
    Lee, Ju Y.; Yang, Sung-Tae; Lee, Seung K.; Jung, Hyun H.; Shin, Song Y.; Hahm, Kyung-Soo; Kim, Jae I.
    FEBS Journal (2008), 275 (15), 3911-3920CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)
    The cathelicidin antimicrobial peptide bactenecin is a β-hairpin mol. with a single disulfide bond and broad antimicrobial activity. The proform of bactenecin exists as a dimer, however, and it has been proposed that bactenecin is released as a dimer in vivo, although there has been little study of the dimeric form of bactenecin. To investigate the effect of bactenecin dimerization on its biol. activity, the authors characterized the dimer's effect on phospholipid membranes, the kinetics of its bactericidal activity, and its salt sensitivity. The authors initially synthesized two bactenecin dimers (antiparallel and parallel) and two monomers (β-hairpin and linear). Under oxidative folding conditions, reduced linear bactenecin preferentially folded into a dimer forming a ladder-like structure via intermol. disulfide bonding. As compared to the monomer, the dimer had a greater ability to induce lysis of lipid bilayers and was more rapidly bactericidal. Interestingly, the dimer retained antimicrobial activity at physiol. salt concns. (150 mM NaCl), although the monomer was inactivated. This salt resistance was also seen with bactenecin dimer contg. one intermol. disulfide bond, and the bactenecin dimer appears to undergo multimeric oligomerization at high salt concns. Overall, dimeric bactenecin shows potent and rapid antimicrobial activity, and resists salt-induced inactivation under physiol. conditions through condensation and oligomerization. These characteristics shed light on the features that a peptide would need to serve as an effective therapeutic agent.
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  71. 71
    King, T. P.; Zhao, S. W.; Lam, T. Preparation of protein conjugates via intermolecular hydrazone linkage. Biochemistry 1986, 25, 5774– 5779,  DOI: 10.1021/bi00367a064
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    71
    Preparation of protein conjugates via intermolecular hydrazone linkage
    King, Te Piao; Zhao, Shu Wei; Lam, Terence
    Biochemistry (1986), 25 (19), 5774-9CODEN: BICHAW; ISSN:0006-2960.
    Proteins can be modified at their amino groups under gentle conditions to produce derivs. contg. an av. of 3-6 aryl aldehyde or acyl hydrazide groups. These 2 types of modified proteins at ∼10 μM concn. condense with each other at pH ∼5 to form conjugates linked by hydrazone bonds. Under proper conditions, conjugates contg. mainly dimers and trimers or, if desired, higher oligomers can be obtained. The conjugates can be dissocd. to their individual protein components by an exchange reaction with an excess of acetyl hydrazide. The reversible hydrazone bonds of conjugates can be reduced with NaCNBH3 to give stable hydrazide bonds. The stability of protein-hydrazone conjugates was significantly greater than that of the model compd., the N-acetylhydrazone of p-carboxybenzaldehyde. This difference is believed to result from the presence of multiple hydrazone linkages in protein conjugates.
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  72. 72
    Rádis-Baptista, G. Cell-Penetrating Peptides Derived from Animal Venoms and Toxins. Toxins 2021, 13, 147– 225,  DOI: 10.3390/toxins13020147
    [Crossref], [PubMed], [CAS], Google Scholar
    72
    Cell-penetrating peptides derived from animal venoms and toxins
    Radis-Baptista, Gandhi
    Toxins (2021), 13 (2), 147CODEN: TOXIB7; ISSN:2072-6651. (MDPI AG)
    A review. Cell-penetrating peptides (CPPs) comprise a class of short polypeptides that possess the ability to selectively interact with the cytoplasmic membrane of certain cell types, translocate across plasma membranes and accumulate in the cell cytoplasm, organelles (e.g., the nucleus and mitochondria) and other subcellular compartments. CPPs are either of natural origin or de novo designed and synthesized from segments and patches of larger proteins or designed by algorithms. With such intrinsic properties, along with membrane permeation, translocation and cellular uptake properties, CPPs can intracellularly convey diverse substances and nanomaterials, such as hydrophilic org. compds. and drugs, macromols. (nucleic acids and proteins), nanoparticles (nanocrystals and polyplexes), metals and radionuclides, which can be covalently attached via CPP N- and C-terminals or through prepn. of CPP complexes. A cumulative no. of studies on animal toxins, primarily isolated from the venom of arthropods and snakes, have revealed the cell-penetrating activities of venom peptides and toxins, which can be harnessed for application in biomedicine and pharmaceutical biotechnol. In this review, I aimed to collate examples of peptides from animal venoms and toxic secretions that possess the ability to penetrate diverse types of cells. These venom CPPs have been chem. or structurally modified to enhance cell selectivity, bioavailability and a range of target applications. Herein, examples are listed and discussed, including cysteine-stabilized and linear, a-helical peptides, with cationic and amphipathic character, from the venom of insects (e.g., melittin, anoplin, mastoparans), arachnids (latarcin, lycosin, chlorotoxin, maurocalcine/imperatoxin homologs and wasabi receptor toxin), fish (pardaxins), amphibian (bombesin) and snakes (crotamine and cathelicidins).
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  73. 73
    Huerta-Cantillo, J.; Navarro-García, F. Properties and design of antimicrobial peptides as potential tools against pathogens and malignant cells. Investig. en Discapac. 2016, 5, 96– 115
    Google Scholar
    There is no corresponding record for this reference.
  74. 74
    Dudek, M.; Romanowska, J.; Wituła, T.; Trylska, J. Interactions of amikacin with the RNA model of the ribosomal A-site: Computational, spectroscopic and calorimetric studies. Biochimie 2014, 102, 188– 202,  DOI: 10.1016/j.biochi.2014.03.009
    [Crossref], [PubMed], [CAS], Google Scholar
    74
    Interactions of amikacin with the RNA model of the ribosomal A-site: Computational, spectroscopic and calorimetric studies
    Dudek, Marta; Romanowska, Julia; Witula, Tomasz; Trylska, Joanna
    Biochimie (2014), 102 (), 188-202CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)
    Amikacin is a 2-deoxystreptamine aminoglycoside antibiotic possessing a unique L-HABA (L-(-)-γ-amino-α-hydroxybutyric acid) group and applied in the treatment of hospital-acquired infections. Amikacin influences bacterial translation by binding to the decoding region of the small ribosomal subunit that overlaps with the binding site of aminoacylated-tRNA (A-site). Here, we have characterized thermodn. of interactions of amikacin with a 27-mer RNA oligonucleotide mimicking the aminoglycoside binding site in the bacterial ribosome. We applied isothermal titrn. and differential scanning calorimetries, CD and thermal denaturation expts., as well as computer simulations. Thermal denaturation studies have shown that amikacin affects only slightly the melting temps. of the A-site mimicking RNA model suggesting a moderate stabilization of RNA by amikacin. Isothermal titrn. calorimetry gives the equil. dissocn. consts. for the binding reaction between amikacin and the A-site oligonucleotide in the micromolar range with a favorable enthalpic contribution. However, for amikacin we observe a pos. entropic contribution to binding, contrary to other aminoglycosides, paromomycin and ribostamycin. CD spectra suggest that the obsd. increase in entropy is not caused by structural changes of RNA because amikacin binding does not destabilize the helicity of the RNA model. To investigate the origins of this pos. entropy change we performed all-atom mol. dynamics simulations in explicit solvent for the 27-mer RNA oligonucleotide mimicking one A-site and the crystal structure of an RNA duplex contg. two A-sites. We obsd. that the diversity of the conformational states of the L-HABA group sampled in the simulations of the complex was larger than for the free amikacin in explicit water. Therefore, the larger flexibility of the L-HABA group in the bound form may contribute to an increase of entropy upon binding.
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  75. 75
    Pilch, D. S.; Kaul, M.; Barbieri, C. M.; Kerrigan, J. E.; Johnson, W. Thermodynamics of aminoglycoside-rRNA recognition. Biopolymers 2003, 70, 58– 79,  DOI: 10.1002/bip.10411
    [Crossref], [PubMed], [CAS], Google Scholar
    75
    Thermodynamics of aminoglycoside-rRNA recognition
    Pilch, Daniel S.; Kaul, Malvika; Barbieri, Christopher M.; Kerrigan, John E.
    Biopolymers (2003), 70 (1), 58-79CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
    2-Deoxystreptamine (2-DOS) aminoglycosides are a family of structurally related broad-spectrum antibiotics that are used widely in the treatment of infections caused by aerobic Gram-neg. bacilli. Their antibiotic activities are ascribed to their abilities to bind a highly conserved A site in the 16S rRNA of the 30S ribosomal subunit and interfere with protein synthesis. The abilities of the 2-DOS aminoglycosides to recognize a specific subdomain of a large RNA mol. make these compds. archetypical models for RNA-targeting drugs. This article presents a series of calorimetric, spectroscopic, osmotic stress, and computational studies designed to evaluate the thermodn. (ΔG, ΔH, ΔS, ΔCp) of aminoglycoside-rRNA interactions, as well as the hydration changes that accompany these interactions. In conjunction with the current structural database, the results of these studies provide important insights into the mol. forces that dictate and control the rRNA binding affinities and specificities of the aminoglycosides. Significantly, identification of these mol. driving forces which include binding-linked drug protonation reactions, polyelectrolyte contributions from counterion release, conformational changes, hydration effects, and mol. interactions (e.g., hydrogen bonds and van der Waals interactions), as well as the relative magnitudes of their contributions to the binding free energy, could not be achieved by consideration of structural data alone, highlighting the importance of acquiring both thermodn. and structural information for developing a complete understanding of the drug-RNA binding process. The results presented here begin to establish a database that can be used to predict, over a range of conditions, the relative affinity of a given aminoglycoside or aminoglycoside mimetic for a targeted RNA site vs. binding to potential competing secondary sites. This type of predictive capability is essential for establishment of a rational design approach to the development of new RNA-targeted drugs.
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  76. 76
    Kulik, M.; Goral, A. M.; Jasiński, M.; Dominiak, P. M.; Trylska, J. Electrostatic interactions in aminoglycoside-RNA complexes. Biophys. J. 2015, 108, 655– 665,  DOI: 10.1016/j.bpj.2014.12.020
    [Crossref], [PubMed], [CAS], Google Scholar
    76
    Electrostatic Interactions in Aminoglycoside-RNA Complexes
    Kulik, Marta; Goral, Anna M.; Jasinski, Maciej; Dominiak, Paulina M.; Trylska, Joanna
    Biophysical Journal (2015), 108 (3), 655-665CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
    Electrostatic interactions often play key roles in the recognition of small mols. by nucleic acids. An example is aminoglycoside antibiotics, which by binding to rRNA affect bacterial protein synthesis. These antibiotics remain one of the few valid treatments against hospital-acquired infections by Gram-neg. bacteria. It is necessary to understand the amplitude of electrostatic interactions between aminoglycosides and their rRNA targets to introduce aminoglycoside modifications that would enhance their binding or to design new scaffolds. Here, we calcd. the electrostatic energy of interactions and its per-ring contributions between aminoglycosides and their primary rRNA binding site. We applied either the methodol. based on the exact potential multipole moment (EPMM) or classical mol. mechanics force field single-point partial charges with Coulomb formula. For EPMM, we first reconstructed the aspherical electron d. of 12 aminoglycoside-RNA complexes from the at. parameters deposited in the University at Buffalo Databank. The University at Buffalo Databank concept assumes transferability of electron d. between atoms in chem. equiv. vicinities and allows reconstruction of the electron densities from exptl. structural data. From the electron d., we then calcd. the electrostatic energy of interaction using EPMM. Finally, we compared the two approaches. The calcd. electrostatic interaction energies between various aminoglycosides and their binding sites correlate with exptl. obtained binding free energies. Based on the calcd. energetic contributions of water mols. mediating the interactions between the antibiotic and rRNA, we suggest possible modifications that could enhance aminoglycoside binding affinity.
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  77. 77
    Protocols for the Fmoc SPPS of Cysteine-containing Peptides. https://www.sigmaaldrich.com/PL/pl/technical-documents/protocol/chemistry-and-synthesis/peptide-synthesis/fmoc-spps-cysteine-peptides#disulfide (Accessed Jan 10, 2022).
    Google Scholar
    There is no corresponding record for this reference.
  78. 78
    Chen, L.; Annis, I.; Barany, G. Disulfide Bond Formation in Peptides. Curr. Protoc. Protein Sci. 2001, 23, 18.16.11– 18.16.19,  DOI: 10.1002/0471140864.ps1806s23
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  79. 79
    Castillo, J. I.; Równicki, M.; Wojciechowska, M.; Trylska, J. Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics on E. coli bacteria. Bioorg. Med. Chem. Lett. 2018, 28, 3094– 3098,  DOI: 10.1016/j.bmcl.2018.07.037
    [Crossref], [PubMed], [CAS], Google Scholar
    79
    Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics in E. coli
    Castillo, Jaime I.; Rownicki, Marcin; Wojciechowska, Monika; Trylska, Joanna
    Bioorganic & Medicinal Chemistry Letters (2018), 28 (18), 3094-3098CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A combination of antibacterial agents should make the emergence of resistance in bacteria less probable. Thus we have analyzed the synergistic effects between antibacterial antisense peptide nucleic acids (PNA) and conventional antibiotics against Escherichia coli AS19 (lipopolysaccharide defective) strain and a deriv. of a pathogenic strain E. coli O157:H7. PNAs were designed to target mRNA transcripts encoding the essential acyl carrier protein (gene acpP) and conjugated to the cell-penetrating peptide (KFF)3K for cellular uptake. Antibiotics included aminoglycosides, aminopenicillins, polymyxins, rifamycins, sulfonamides and trimethoprim. Synergies were evaluated using the checkerboard technique. Fractional Inhibitory Concn. indexes (FICi) were calcd. for all combinations based on the minimal inhibitory concn. of each individual agent. The results demonstrate two novel synergistic combinations of antimicrobial agents, namely, (KFF)3K-PNA anti-acpP with polymyxin B and (KFF)3K-PNA anti-acpP with trimethoprim (both with FICi = 0.38). Polymyxin B's synergy postulates cell wall targeted antibiotics as attractive agents to improve the uptake of PNA while trimethoprim's interaction with PNA my reveal a new inhibitory mechanism.
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  80. 80
    Hsieh, M. H.; Yu, C. M.; Yu, V. L.; Chow, J. W. Synergy assessed by checkerboard a critical analysis. Diagn. Microbiol. Infect. Dis. 1993, 16, 343– 349,  DOI: 10.1016/0732-8893(93)90087-n
    [Crossref], [PubMed], [CAS], Google Scholar
    80
    Synergy assessed by checkerboard. A critical analysis
    Hsieh M H; Yu C M; Yu V L; Chow J W
    Diagnostic microbiology and infectious disease (1993), 16 (4), 343-9 ISSN:0732-8893.
    The checkerboard dilution test is widely used for evaluation of in vitro synergy for multiple drugs, although problems in performance, standardization, and interpretation have been noted. A major problem inherent in this commonly used method is the use of twofold dilutions for the antibiotic concentrations. We evaluated an alternative method proposed by Horrevorts and colleagues that preserved the twofold dilution scheme. Giant checkerboards were constructed from a series of component checkerboards using rifampin and minocycline against Staphylococcus aureus. We found that this method improved the stability of the fractional inhibitory concentration (FIC) indices, but required substantially more labor and generated other problems. FIC interpretation and calculation remained compromised by the twofold dilution scheme. We have analyzed the theoretical basis of the checkerboard and its FIC calculation and conclude that the twofold dilution with its exponential increase in dilutions makes this method of synergy evaluation inherently unstable. The principle of examining growth at multiple dilutions of combined antibiotics is valid for assessment of synergy, but newer methods need to be devised.
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  • Abstract

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    Figure 1

    Figure 1. Chemical structures of the elements forming the conjugates: aminoglycosides [amikacin (AMK) and neomycin (NEO)], amphipathic peptides (anoplin and anoplin[2-6]), and the linker type (triazole and disulfide bond). The helical wheel projection (predicted by Heliquest (60)) of the peptides and the positions at which the elements are connected are also shown (red and blue waves).

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    Scheme 1

    Scheme 1. Two-Step Synthesis of the Protected NEO-Pyridyl Disulfidea
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    aReagents and conditions: (a) thiourea, EtOH, reflux, 3 days and (b) 2-mercaptopyridine, MeNH2, MeOH, rt, 18 h. OTPS–─2,4,6 triisopropylbenzenesulfonate.

    Figure 2

    Figure 2. Hemolytic activity of the conjugates against the sheep RBCs. Erythrocytes treated with 1% Triton-X-100 were used as a positive control (100% of hemolysis).

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    1. 1
      Venkatesan, P. WHO 2020 report on the antibacterial production and development pipeline. Lancet Microbe 2021, 2, e239  DOI: 10.1016/s2666-5247(21)00124-5
      [Crossref], [PubMed], Google Scholar
      There is no corresponding record for this reference.
    2. 2
      Sansom, C. Where are the next generation of antibiotics going to come from? https://www.chemistryworld.com/features/the-antibiotic-countdown/3008544.article (accessed Nov 08, 2022).
      Google Scholar
      There is no corresponding record for this reference.
    3. 3
      Ghosh, S.; Bornman, C.; Zafer, M. M. Antimicrobial Resistance Threats in the emerging COVID-19 pandemic: Where do we stand?. J. Infect. Public Health 2021, 14, 555– 560,  DOI: 10.1016/j.jiph.2021.02.011
      [Crossref], [PubMed], [CAS], Google Scholar
      3
      Antimicrobial Resistance Threats in the emerging COVID-19 pandemic: Where do we stand?
      Ghosh Soumya; Bornman Charne; Zafer Mai M
      Journal of infection and public health (2021), 14 (5), 555-560 ISSN:.
      Antimicrobial resistance (AMR) continues to exert a substantial toll on the global health and world economy and is now expected to be hidden by COVID-19 for a while. The wrong consumption of antibiotics during the COVID-19 pandemic will raise disastrous effects on AMR management and antibiotic stewardship programs. This is related to the concerns extrapolated due to an increase in mortality rates in patients with bacterial coinfections. Importantly, the immune system of COVID-19 patients in regions with high AMR may be fighting on two fronts altogether, the virus and MDR bacteria. Current control policies to manage AMR and prioritization of antibiotic stewardship plans are mandatory during this pandemic. This review aims to discuss the rising concerns of the excess use of antibiotics in COVID-19 patients highlighting the role of bacterial coinfections in these patients. Types of prescribed antibiotics and the development of antibiotic resistance is addressed as well.
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    4. 4
      Ma, E. S. K.; Kung, K. H.; Chen, H. Combating antimicrobial resistance during the COVID-19 pandemic. Hong Kong Med. J. 2021, 27, 396– 398,  DOI: 10.12809/hkmj215124
      [Crossref], [PubMed], [CAS], Google Scholar
      4
      Combating antimicrobial resistance during the COVID-19 pandemic
      Ma E S K; Ma E S K; Kung K H; Chen H
      Hong Kong medical journal = Xianggang yi xue za zhi (2021), 27 (6), 396-398 ISSN:1024-2708.
      There is no expanded citation for this reference.
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    5. 5
      Krause, K. M.; Serio, A. W.; Kane, T. R.; Connolly, L. E. Aminoglycosides : An Overview. Cold Spring Harbor Perspect. Med. 2016, 6, a027029,  DOI: 10.1101/cshperspect.a027029
      [Crossref], [PubMed], [CAS], Google Scholar
      5
      Aminoglycosides: an overview
      Krause, Kevin M.; Serio, Alisa W.; Kane, Timothy R.; Connolly, Lynn E.
      Cold Spring Harbor Perspectives in Medicine (2016), 6 (6), a027029/1-a027029/19CODEN: CSHPFV; ISSN:2157-1422. (Cold Spring Harbor Laboratory Press)
      Aminoglycosides are natural or semisynthetic antibiotics derived from actinomycetes. They were among the first antibiotics to be introduced for routine clin. use and several examples have been approved for use in humans. They found widespread use as first-line agents in the early days of antimicrobial chemotherapy, but were eventually replaced in the 1980s with cephalosporins, carbapenems, and fluoroquinolones. Aminoglycosides synergize with a variety of other antibacterial classes, which, in combination with the continued increase in the rise of multidrug-resistant bacteria and the potential to improve the safety and efficacy of the class through optimized dosing regimens, has led to a renewed interest in these broad-spectrum and rapidly bactericidal antibacterials.
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    6. 6
      Houghton, J. L.; Green, K. D.; Chen, W.; Garneau-Tsodikova, S. The future of aminoglycosides: The end or renaissance?. ChemBioChem 2010, 11, 880– 902,  DOI: 10.1002/cbic.200900779
      [Crossref], [PubMed], [CAS], Google Scholar
      6
      The Future of Aminoglycosides: the End or Renaissance?
      Houghton, Jacob L.; Green, Keith D.; Chen, Wenjing; Garneau-Tsodikova, Sylvie
      ChemBioChem (2010), 11 (7), 880-902CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Although aminoglycosides were used as antibacterials for decades, their use was hindered by their inherent toxicity and the resistance that has emerged to these compds. It seems that such issues have relegated a formerly front-line class of antimicrobials to the proverbial back shelf. However, recent advances have demonstrated that novel aminoglycosides have a potential to overcome resistance as well as to be used to treat HIV-1 and even human genetic disorders, with abrogated toxicity. It is not the end for aminoglycosides, but rather, the challenges faced by researchers have led to ingenuity and a change in how we view this class of compds., a renaissance.
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    7. 7
      Becker, B.; Cooper, M. A. Aminoglycoside antibiotics in the 21st century. ACS Chem. Biol. 2013, 8, 105– 115,  DOI: 10.1021/cb3005116
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      7
      Aminoglycoside Antibiotics in the 21st Century
      Becker, Bernd; Cooper, Matthew A.
      ACS Chemical Biology (2013), 8 (1), 105-115CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      A review. Aminoglycoside antibiotics were among the first antibiotics discovered and used clin. Although they have never completely fallen out of favor, their importance has waned due to the emergence of other broad-spectrum antibiotics with fewer side effects. Today, with the dramatically increasing rate of infections caused by multidrug-resistant bacteria, focus has returned to aminoglycoside antibiotics as one of the few remaining treatment options, particularly for Gram-neg. pathogens. Although the mechanisms of resistance are reasonably well understood, our knowledge about the mode of action of aminoglycosides is still far from comprehensive. In the face of emerging bacterial infections that are virtually untreatable, it is time to have a fresh look at this old class to reinvigorate the struggle against multidrug-resistant pathogens.
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    8. 8
      Schatz, A.; Bugie, E.; Waksman, S. A.; Hanssen, A. D.; Patel, R.; Osmon, D. R. . The Classic: Streptomycin, a Substance Exhibiting Antibiotic Activity against Gram-Positive and Gram-Negative Bacteria. Clin. Orthop. Relat. Res. 2005, 437, 3– 6,  DOI: 10.1097/01.blo.0000175887.98112.fe
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    9. 9
      Wang, N.; Luo, J.; Deng, F.; Huang, Y.; Zhou, H. Antibiotic Combination Therapy: A Strategy to Overcome Bacterial Resistance to Aminoglycoside Antibiotics. Front. Pharmacol. 2022, 13, 1– 15,  DOI: 10.3389/fphar.2022.839808
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    10. 10
      Bera, S.; Mondal, D.; Palit, S.; Schweizer, F. Structural modifications of the neomycin class of aminoglycosides. MedChemComm 2016, 7, 1499– 1534,  DOI: 10.1039/c6md00079g
      [Crossref], [CAS], Google Scholar
      10
      Structural modifications of the neomycin class of aminoglycosides
      Bera, Smritilekha; Mondal, Dhananjoy; Palit, Subhadeep; Schweizer, Frank
      MedChemComm (2016), 7 (8), 1499-1534CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
      A review. Clin. used potent broad spectrum bactericidal aminoglycoside (AG) antibiotics have suffered diminished use due to dose-related toxicity and rapid emergence of resistance. To overcome these shortfalls, researchers have performed many structural modifications to the aminoglycoside scaffold. The motivation behind the development of novel aminoglycoside analogs is in part caused by the inability to discover novel antibiotics with new modes of action esp. against Gram-neg. bacteria. As AGs are composed of highly functionalised polycationic oligosaccharides carrying several hydroxy and amino functional groups with an incorporated streptamine unit, numerous synthetic approaches for their fabrication and revitalization have been articulated. Impressive endeavours and advancements made in this direction by researchers across the globe have been well documented in a large vol. of literature. The objective of this review article is to summarize the recent progress in this field in a comprehensive manner paying special attention to the chem. of structurally related neomycin, paromomycin and neamine.
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    11. 11
      Trylska, J.; Kulik, M. Interactions of aminoglycoside antibiotics with rRNA. Biochem. Soc. Trans. 2016, 44, 987– 993,  DOI: 10.1042/bst20160087
      [Crossref], [PubMed], [CAS], Google Scholar
      11
      Interactions of aminoglycoside antibiotics with rRNA
      Trylska, Joanna; Kulik, Marta
      Biochemical Society Transactions (2016), 44 (4), 987-993CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)
      Aminoglycoside antibiotics are protein synthesis inhibitors applied to treat infections caused mainly by aerobic Gram-neg. bacteria. Due to their adverse side effects they are last resort antibiotics typically used to combat pathogens resistant to other drugs. Aminoglycosides target ribosomes. We describe the interactions of aminoglycoside antibiotics contg. a 2-deoxystreptamine (2-DOS) ring with 16S rRNA. We review the computational studies, with a focus on mol. dynamics (MD) simulations performed on RNA models mimicking the 2-DOS aminoglycoside binding site in the small ribosomal subunit. We also briefly discuss thermodn. of interactions of these aminoglycosides with their 16S RNA target.
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    12. 12
      Kotra, L. P.; Haddad, J.; Mobashery, S. Aminoglycosides: Perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob. Agents Chemother. 2000, 44, 3249– 3256,  DOI: 10.1128/aac.44.12.3249-3256.2000
      [Crossref], [PubMed], [CAS], Google Scholar
      12
      Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance
      Kotra, Lakshmi P.; Haddad, Jalal; Mobashery, Shahriar
      Antimicrobial Agents and Chemotherapy (2000), 44 (12), 3249-3256CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      A review with 57 refs.
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    13. 13
      Fourmy, D.; Recht, M. I.; Puglisi, J. D. Binding of neomycin-class aminoglycoside antibiotics to the A-site of 16 S rRNA. J. Mol. Biol. 1998, 277, 347– 362,  DOI: 10.1006/jmbi.1997.1552
      [Crossref], [PubMed], [CAS], Google Scholar
      13
      Binding of neomycin-class aminoglycoside antibiotics to the A-site of 16 S rRNA
      Fourmy, Dominique; Recht, Michael I.; Puglisi, Joseph D.
      Journal of Molecular Biology (1998), 277 (2), 347-362CODEN: JMOBAK; ISSN:0022-2836. (Academic Press Ltd.)
      Aminoglycoside antibiotics that bind to rRNA in the aminoacyl-tRNA site (A-site) cause misreading of the genetic code and inhibit translocation. We have recently solved the structure of an A-site RNA-paromomycin complex. The structure suggested that rings I and II, common to all aminoglycosides that bind to the A-site, are the min. motif for specific ribosome binding to affect translation. This hypothesis was tested biochem. and with a detailed comparative NMR study of interaction of the aminoglycosides paromomycin, neomycin, ribostamycin, and neamine with the A-site RNA. Our NMR data show that rings I and II of neomycin-class aminoglycosides are sufficient to confer specificity to the binding of the antibiotics to the model A-site RNA. Neomycin, paromomycin, ribostamycin and neamine bind in the major groove of the A-site RNA in a unique binding pocket formed by non-canonical base pairs and a bulged nucleotide. Similar NMR properties of the RNA and the diverse antibiotics within the different complexes formed with neomycin, paromomycin, ribostamycin and neamine suggest similar structures for these complexes.
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    14. 14
      Maxwell, A.; Ghate, V.; Aranjani, J.; Lewis, S. Breaking the barriers for the delivery of amikacin: Challenges, strategies, and opportunities. Life Sci. 2021, 284, 119883,  DOI: 10.1016/j.lfs.2021.119883
      [Crossref], [PubMed], [CAS], Google Scholar
      14
      Breaking the barriers for the delivery of amikacin: Challenges, strategies, and opportunities
      Maxwell, Amala; Ghate, Vivek; Aranjani, Jesil; Lewis, Shaila
      Life Sciences (2021), 284 (), 119883CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
      A review. Hypodermic delivery of amikacin is a widely adopted treatment modality for severe infections, including bacterial septicemia, meningitis, intra-abdominal infections, burns, postoperative complications, and urinary tract infections in both paediatric and adult populations. In most instances, the course of treatment requires repeated bolus doses of amikacin, prolonged hospitalization, and the presence of a skilled healthcare worker for administration and continuous therapeutic monitoring to manage the severe adverse effects. Amikacin is hydrophilic and exhibits a short half-life, which further challenges the delivery of sufficient systemic concns. when administered by the oral or transdermal route. In this purview, the exploitation of novel controlled and sustained release drug delivery platforms is warranted. Furthermore, it has been shown that novel delivery systems are capable of increasing the antibacterial activity of amikacin at lower doses when compared to the conventional formulations and also aid in overcoming the development of drug-resistance, which currently is a significant threat to the healthcare system worldwide. The current review presents a comprehensive overview of the developmental history of amikacin, the mechanism of action in virulent strains as well as the occurrence of resistance, and various emerging drug delivery solns. developed both by the academia and the industry. The examples outlined within the review provides significant pieces of evidence on novel amikacin formulations in the field of antimicrobial research paving the path for future therapeutic interventions that will result in improved clin. outcome.
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    15. 15
      Vakulenko, S. B.; Mobashery, S. Versatility of aminoglycosides and prospects for their future. Clin. Microbiol. Rev. 2003, 16, 430– 450,  DOI: 10.1128/cmr.16.3.430-450.2003
      [Crossref], [PubMed], [CAS], Google Scholar
      15
      Versatility of aminoglycosides and prospects for their future
      Vakulenko, Sergei B.; Mobashery, Shahriar
      Clinical Microbiology Reviews (2003), 16 (3), 430-450CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
      A review. Aminoglycoside antibiotics have had a major impact on our ability to treat bacterial infections for the past half century. Whereas the interest in these versatile antibiotics continues to be high, their clin. utility has been compromised by widespread instances of resistance. The multitude of mechanisms of resistance is disconcerting but also illuminates how Nature can manifest resistance when bacteria are confronted by antibiotics. This article reviews the most recent knowledge about the mechanisms of aminoglycoside action and the mechanisms of resistance to these antibiotics.
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    16. 16
      Tevyashova, A. N.; Shapovalova, K. S. Potential for the Development of a New Generation of Aminoglycoside Antibiotics. Pharm. Chem. J. 2021, 55, 860– 875,  DOI: 10.1007/s11094-021-02510-0
      [Crossref], [PubMed], [CAS], Google Scholar
      16
      Potential for the Development of a New Generation of Aminoglycoside Antibiotics
      Tevyashova, A. N.; Shapovalova, K. S.
      Pharmaceutical Chemistry Journal (2021), 55 (9), 860-875CODEN: PCJOAU; ISSN:0091-150X. (Springer)
      A review. The present review summarizes recent publications devoted to aminoglycosides that study the main types of resistance to antibiotics of this class and the main directions of chem. modification aimed at overcoming the resistance or changing the spectrum of biol. activity. Conjugates of aminoglycosides with various pharmacophores including amino acids, peptides, peptide nucleic acids, nucleic bases, and several other biol. active mols. and modifications resulting in other types of biol. activity of this class of antibiotics are described. It is concluded that a promising research direction aimed at increasing the activity of antibiotics against resistant strains is the search for selective inhibitors of aminoglycoside-modifying enzymes. This would allow renewal of the use of antibiotics already meeting widespread resistance and would increase the potential of a new generation of antibiotics.
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    17. 17
      Udumula, V.; Ham, Y. W.; Fosso, M. Y.; Chan, K. Y.; Rai, R.; Zhang, J.; Li, J.; Chang, C. W. T. Investigation of antibacterial mode of action for traditional and amphiphilic aminoglycosides. Bioorg. Med. Chem. Lett. 2013, 23, 1671– 1675,  DOI: 10.1016/j.bmcl.2013.01.073
      [Crossref], [PubMed], [CAS], Google Scholar
      17
      Investigation of antibacterial mode of action for traditional and amphiphilic aminoglycosides
      Udumula, Venkatareddy; Ham, Young Wan; Fosso, Marina Y.; Chan, Ka Yee; Rai, Ravi; Zhang, Jianjun; Li, Jie; Chang, Cheng-Wei Tom
      Bioorganic & Medicinal Chemistry Letters (2013), 23 (6), 1671-1675CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Aminoglycoside represents a class of versatile and broad spectrum antibacterial agents. In an effort to revive the antibacterial activity against aminoglycoside resistant bacteria, our lab. has developed two new classes of aminoglycoside, pyranmycin and amphiphilic neomycin (NEOF004). The former resembles the traditional aminoglycoside, neomycin. The latter, albeit derived from neomycin, appears to exert antibacterial action via a different mode of action. In order to discern that these aminoglycoside derivs. have distinct antibacterial mode of action, RNA-binding affinity and fluorogenic dye were employed. These studies, together with our previous investigation, confirm that pyranmycin exhibit the traditional antibacterial mode of action of aminoglycosides by binding toward the bacterial rRNA. On the other hand, the amphiphilic neomycin, NEOF004 disrupts the bacterial cell wall. In a broader perspective, it verifies that structurally modified neomycin can exert different antibacterial mode of action leading to the revival of activity against aminoglycoside resistant bacteria.
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    18. 18
      Aradi, K.; Di Giorgio, A.; Duca, M. Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond. Chem.─Eur. J. 2020, 26, 12273– 12309,  DOI: 10.1002/chem.202002258
      [Crossref], [PubMed], [CAS], Google Scholar
      18
      Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond
      Aradi, Klara; Di Giorgio, Audrey; Duca, Maria
      Chemistry - A European Journal (2020), 26 (54), 12273-12309CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Natural aminoglycosides are therapeutically useful antibiotics and very efficient RNA ligands. They are oligosaccharides that contain several ammonium groups able to interfere with the translation process in prokaryotes upon binding to bacterial rRNA, and thus, impairing protein synthesis. Even if aminoglycosides are commonly used in therapy, these RNA binders lack selectivity and are able to bind to a wide no. of RNA sequences/structures. This is one of the reasons for their toxicity and limited applications in therapy. At the same time, the ability of aminoglycosides to bind to various RNAs renders them a great source of inspiration for the synthesis of new binders with improved affinity and specificity toward several therapeutically relevant RNA targets. Thus, a no. of studies have been performed on these complex and highly functionalized compds., leading to the development of various synthetic methodologies toward the synthesis of conjugated aminoglycosides. The aim of this review is to highlight recent progress in the field of aminoglycoside conjugation, paying particular attention to modifications performed toward the improvement of affinity and esp. to the selectivity of the resulting compds. This will help readers to understand how to introduce a desired chem. modification for future developments of RNA ligands as antibiotics, antiviral, and anticancer compds.
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    19. 19
      Chandrika, T. N.; Garneau-Tsodikova, S. Comprehensive Review of Chemical Strategies for the Preparation of New Aminoglycosides and their Biological Activities. Chem. Soc. Rev. 2018, 47, 1189– 1249,  DOI: 10.1039/c7cs00407a
      [Crossref], [PubMed], Google Scholar
      There is no corresponding record for this reference.
    20. 20
      Kato, T.; Yang, G.; Teo, Y.; Juskeviciene, R.; Perez-Fernandez, D.; Shinde, H. M.; Salian, S.; Bernet, B.; Vasella, A.; Böttger, E. C.; Crich, D. Synthesis and Antiribosomal Activities of 4′-O-6′-O-4″-O-4′,6′-O- and 4″,6″-O-Derivatives in the Kanamycin Series Indicate Differing Target Selectivity Patterns between the 4,5- and 4,6-Series of Disubstituted 2-Deoxystreptamine Aminoglycoside Antibiotics. ACS Infect. Dis. 2015, 1, 479– 486,  DOI: 10.1021/acsinfecdis.5b00069
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      20
      Synthesis and Antiribosomal Activities of 4'-O-, 6'-O-, 4''-O-, 4',6'-O- and 4'',6''-O-Derivatives in the Kanamycin Series Indicate Differing Target Selectivity Patterns between the 4,5- and 4,6-Series of Disubstituted 2-Deoxystreptamine Aminoglycoside Antibiotics
      Kato, Takayuki; Yang, Guanyu; Teo, Youjin; Juskeviciene, Reda; Perez-Fernandez, Deborah; Shinde, Harish M.; Salian, Sumanth; Bernet, Bruno; Vasella, Andrea; Bottger, Erik C.; Crich, David
      ACS Infectious Diseases (2015), 1 (10), 479-486CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      Chem. for the efficient modification of the kanamycin class of 4,6-aminoglycosides at the 4'-position is presented. In all kanamycins but kanamycin B, 4'-O-alkylation is strongly detrimental to antiribosomal and antibacterial activity. Ethylation of kanamycin B at the 4''-position entails little loss of antiribosomal and antibacterial activity, but no increase of ribosomal selectivity. These results are contrasted with those for the 4,5-aminoglycosides, where 4'-O-alkylation of paromomycin causes only a minimal loss of activity but results in a significant increase in selectivity with a concomitant loss of ototoxicity.
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    21. 21
      Zhang, J.; Keller, K.; Takemoto, J. Y.; Bensaci, M.; Litke, A.; Czyryca, P. G.; Chang, C. W. T. Synthesis and combinational antibacterial study of 5″-modified neomycin. J. Antibiot. 2009, 62, 539– 544,  DOI: 10.1038/ja.2009.66
      [Crossref], [PubMed], [CAS], Google Scholar
      21
      Synthesis and combinational antibacterial study of 5''-modified neomycin
      Zhang, Jianjun; Keller, Katherine; Takemoto, Jon Y.; Bensaci, Mekki; Litke, Anthony; Czyryca, Przemyslaw Greg; Chang, Cheng-Wei Tom
      Journal of Antibiotics (2009), 62 (10), 539-544CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)
      A library of 5''-modified neomycin derivs. were synthesized for an antibacterial structure-activity optimization strategy. Two leads exhibited prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clin. used antibiotics. Significant synergistic activities were obsd., which may lead to the development of novel therapeutic practices in the battle against infectious bacteria.
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    22. 22
      Zhang, J.; Chiang, F. I.; Wu, L.; Czyryca, P. G.; Li, D.; Chang, C. W. T. Surprising alteration of antibacterial activity of 5″-modified neomycin against resistant bacteria. J. Med. Chem. 2008, 51, 7563– 7573,  DOI: 10.1021/jm800997s
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      22
      Surprising Alteration of Antibacterial Activity of 5''-Modified Neomycin against Resistant Bacteria
      Zhang, Jianjun; Chiang, Fang-I.; Wu, Long; Czyryca, Przemyslaw Greg; Li, Ding; Chang, Cheng-Wei Tom
      Journal of Medicinal Chemistry (2008), 51 (23), 7563-7573CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A facile synthetic protocol for the prodn. of neomycin B derivs. with various modifications at the 5'' position has been developed. The structural activity relation (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymic and mol. modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivs. show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivs. against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clin. used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biol. and antimicrobial activities can be obtained by chem. modifications of old drugs.
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    23. 23
      Martin, C.; Bonnet, M.; Patino, N.; Azoulay, S.; Di Giorgio, A.; Duca, M. Design, synthesis and evaluation of neomycin-imidazole conjugates for RNA cleavage. Chempluschem 2022, 87, 49– 58,  DOI: 10.1002/cplu.202200250
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    24. 24
      Bera, S.; Zhanel, G. G.; Schweizer, F. Design, synthesis, and antibacterial activities of neomycin-lipid conjugates: Polycationic lipids with potent gram-positive activity. J. Med. Chem. 2008, 51, 6160– 6164,  DOI: 10.1021/jm800345u
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      24
      Design, Synthesis, and Antibacterial Activities of Neomycin-Lipid Conjugates: Polycationic Lipids with Potent Gram-Positive Activity
      Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
      Journal of Medicinal Chemistry (2008), 51 (19), 6160-6164CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Aminoglycoside antibiotics and cationic detergents constitute two classes of important drugs and antiseptics. Their bacterial efficacy has decreased recently due to antibiotic resistance. We have synthesized aminoglycoside-lipid conjugates in which the aminoglycoside neomycin forms the cationic headgroup of a polycationic detergent. Our results show that neomycin-C16 and neomycin-C20 conjugates exhibit strong Gram-pos. activity but reduced Gram-neg. activity. The MIC of neomycin-C16 (C20) conjugates against methicillin-resistant Staphylococcus aureus (MRSA) is comparable to known antiseptics.
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    25. 25
      Bera, S.; Zhanel, G. G.; Schweizer, F. Evaluation of amphiphilic aminoglycoside-peptide triazole conjugates as antibacterial agents. Bioorg. Med. Chem. Lett. 2010, 20, 3031– 3035,  DOI: 10.1016/j.bmcl.2010.03.116
      [Crossref], [PubMed], [CAS], Google Scholar
      25
      Evaluation of amphiphilic aminoglycoside-peptide triazole conjugates as antibacterial agents
      Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
      Bioorganic & Medicinal Chemistry Letters (2010), 20 (10), 3031-3035CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      The solid- and soln.-phase synthesis of amphiphilic aminoglycoside-peptide triazole conjugates (APTCs) accessed by copper(I)-catalyzed 1,3-dipolar cycloaddn. reaction between a hydrophobic and ultrashort peptide-based alkyne and a neomycin B- or kanamycin A-derived azide is presented. Antibacterial evaluation demonstrates that the antibacterial potency is affected by the nature of the peptide component. Several APTCs exhibit superior activity against neomycin B- and kanamycin A-resistant strains when compared to their parent aminoglycoside while displaying reduced activity against neomycin B- and kanamycin A-susceptible strains.
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    26. 26
      Bera, S.; Zhanel, G. G.; Schweizer, F. Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates. Carbohydr. Res. 2011, 346, 560– 568,  DOI: 10.1016/j.carres.2011.01.015
      [Crossref], [PubMed], [CAS], Google Scholar
      26
      Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates
      Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
      Carbohydrate Research (2011), 346 (5), 560-568CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
      Amphiphilic lysine-ligated neomycin B building blocks were prepd. by reductive amination of a protected C5''-modified neomycin B-based aldehyde and side chain-unprotected lysine or lysine-contg. peptides. It was demonstrated that a suitably protected lysine-ligated neomycin B conjugate (NeoK) serves as a building block for peptide synthesis, enabling incorporation of aminoglycoside binding sites into peptides. Antibacterial testing of three amphiphilic lysine-ligated neomycin B conjugates against a representative panel of Gram-pos. and Gram-neg. strains demonstrates that C5''-modified neomycin-lysine conjugate retains antibacterial activity. However, in most cases the lysine-ligated neomycin B analogs display reduced potency against Gram-pos. strains when compared to unmodified neomycin B or unligated peptide. An exception is MRSA where an eightfold enhancement was obsd. When compared to unmodified neomycin B, the prepd. lysine-neomycin conjugates exhibited a 4-8-fold enhanced Gram-neg. activity against Pseudomonas aeruginosa and up to 12-fold enhanced activity was obsd. when compared to unligated ref. peptides.
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    27. 27
      Fair, R. J.; McCoy, L. S.; Hensler, M. E.; Aguilar, B.; Nizet, V.; Tor, Y. Singly modified amikacin and tobramycin derivatives show increased rRNA A-site binding and higher potency against resistant bacteria. ChemMedChem 2014, 9, 2164– 2171,  DOI: 10.1002/cmdc.201402175
      [Crossref], [PubMed], [CAS], Google Scholar
      27
      Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A-Site Binding and Higher Potency against Resistant Bacteria
      Fair, Richard J.; McCoy, Lisa S.; Hensler, Mary E.; Aguilar, Bernice; Nizet, Victor; Tor, Yitzhak
      ChemMedChem (2014), 9 (9), 2164-2171CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Semisynthetic derivs. of the clin. useful aminoglycosides tobramycin and amikacin were prepd. by selectively modifying their 6'' positions with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A-site was probed using an in vitro FRET-based assay, and their antibacterial activities against several resistant strains (e.g., Pseudomonas aeruginosa, Klebsiella pneumonia, MRSA) were quantified by detg. min. inhibitory concns. (MICs). The most potent derivs. were evaluated for their eukaryotic cytotoxicity. Most analogs displayed higher affinity for the bacterial A-site than the parent compds. Although most tobramycin analogs exhibited no improvement in antibacterial activity, several amikacin analogs showed potent and broad-spectrum antibacterial activity against resistant bacteria. Derivs. tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compds.
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    28. 28
      Shai, Y. Mode of action of membrane active antimicrobial peptides. Biopolymers 2002, 66, 236– 248,  DOI: 10.1002/bip.10260
      [Crossref], [PubMed], [CAS], Google Scholar
      28
      Mode of action of membrane active antimicrobial peptides
      Shai, Yechiel
      Biopolymers (2002), 66 (4), 236-248CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
      A review. Water-membrane sol. protein and peptide toxins are used in the defense and offense systems of all organisms, including plants and humans. A major group includes antimicrobial peptides, which serve as a nonspecific defense system that complements the highly specific cell-mediated immune response. The increasing resistance of bacteria to conventional antibiotics stimulated the isolation and characterization of many antimicrobial peptides for potential use as new target antibiotics. The finding of thousands of antimicrobial peptides with variable lengths and sequences, all of which are active at similar concns., suggests a general mechanism for killing bacteria rather than a specific mechanism that requires preferred active structures. Such a mechanism is in agreement with the carpet model that does not require any specific structure or sequence. It seems that when there is an appropriate balance between hydrophobicity and a net pos. charge the peptides are active on bacteria. However, selective activity depends also on other parameters, such as the vol. of the mol., its structure, and its oligomeric state in soln. and membranes. Further, although many studies support that bacterial membrane damage is a lethal event for bacteria, other studies point to a multihit mechanism in which the peptide binds to several targets in the cytoplasmic region of the bacteria.
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    29. 29
      Mojsoska, B.; Jenssen, H. Peptides and peptidomimetics for antimicrobial drug design. Pharmaceuticals 2015, 8, 366– 415,  DOI: 10.3390/ph8030366
      [Crossref], [PubMed], [CAS], Google Scholar
      29
      Peptides and peptidomimetics for antimicrobial drug design
      Mojsoska, Biljana; Jenssen, Haavard
      Pharmaceuticals (2015), 8 (3), 366-415CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)
      The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies. After first dissecting the important physiochem. properties that influence the antimicrobial and toxic properties of antimicrobial peptides, the contributions of individual amino acids with respect to the peptides antibacterial properties are presented. A brief discussion of the mechanisms of action of different antimicrobials as well as the development of bacterial resistance towards antimicrobial peptides follows. Finally, current efforts on novel design strategies and peptidomimetics are introduced to illustrate the importance of antimicrobial peptide research in the development of future antibiotics.
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    30. 30
      Wang, G.; Li, X.; Wang, Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 2016, 44, D1087– D1093,  DOI: 10.1093/nar/gkv1278
      [Crossref], [PubMed], [CAS], Google Scholar
      30
      APD3: the antimicrobial peptide database as a tool for research and education
      Wang, Guangshun; Li, Xia; Wang, Zhe
      Nucleic Acids Research (2016), 44 (D1), D1087-D1093CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      The antimicrobial peptide database (APD, http://aps. unmc.edu/AP/) is an original database initially online in 2003. The APD2 (2009 version) has been regularly updated and further expanded into the APD3. This database currently focuses on natural antimicrobial peptides (AMPs) with defined sequence and activity. It includes a total of 2619 AMPs with 261 bacteriocins from bacteria, 4 AMPs from archaea, 7 from protists, 13 from fungi, 321 from plants and 1972 animal host defense peptides. The APD3 contains 2169 antibacterial, 172 antiviral, 105 anti-HIV, 959 antifungal, 80 antiparasitic and 185 anticancer peptides. Newly annotated are AMPswith antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties. We also describe other searchable annotations, including target pathogens, mol.-binding partners, post-translational modifications and animal models. Amino acid profiles or signatures of natural AMPs are important for peptide classification, prediction and design. Finally, we summarize various database applications in research and education.
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    31. 31
      Lai, Z.; Yuan, X.; Chen, H.; Zhu, Y.; Dong, N.; Shan, A. Strategies employed in the design of antimicrobial peptides with enhanced proteolytic stability. Biotechnol. Adv. 2022, 59, 107962,  DOI: 10.1016/j.biotechadv.2022.107962
      [Crossref], [PubMed], [CAS], Google Scholar
      31
      Strategies employed in the design of antimicrobial peptides with enhanced proteolytic stability
      Lai, Zhenheng; Yuan, Xiaojie; Chen, Hongyu; Zhu, Yunhui; Dong, Na; Shan, Anshan
      Biotechnology Advances (2022), 59 (), 107962CODEN: BIADDD; ISSN:0734-9750. (Elsevier Inc.)
      A review. Due to the alarming developing rate of multidrug-resistant bacterial pathogens, the development and modification of antimicrobial peptides (AMPs) are unprecedentedly active. Despite the fact that considerable efforts have been expended on the discovery and design strategies of AMPs, the clin. translation of peptide antibiotics remains inadequate. A large no. of articles and reviews credited the limited success of AMPs to their poor stability in the biol. environment, particularly their poor proteolytic stability. In the past forty years, various design strategies have been used to improve the proteolytic stability of AMPs, such as sequence modification, cyclization, peptidomimetics, and nanotechnol. Herein, we focus our discussion on the progress made in improving the proteolytic stability of AMPs and the principle, successes, and limitations of various anti-proteolytic design strategies. It is of prospective significance to extend current insights into the degrdn.-related inactivation of AMPs and also alleviate/overcome the problem.
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    32. 32
      Gan, B. H.; Gaynord, J.; Rowe, S. M.; Deingruber, T.; Spring, D. R. The multifaceted nature of antimicrobial peptides: Current synthetic chemistry approaches and future directions. Chem. Soc. Rev. 2021, 50, 7820– 7880,  DOI: 10.1039/d0cs00729c
      [Crossref], [PubMed], [CAS], Google Scholar
      32
      The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions
      Gan, Bee Ha; Gaynord, Josephine; Rowe, Sam M.; Deingruber, Tomas; Spring, David R.
      Chemical Society Reviews (2021), 50 (13), 7820-7880CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Bacterial infections caused by primesuperbugsprime are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clin. potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochem. properties, mechanisms of action, and effects of environmental factors on these features. This review outlines various chem. synthetic strategies that have been applied to develop novel AMPs, including chem. modifications of existing peptides, semi-synthesis, and computer-aided design. We will also highlight novel AMP structures, including hybrids, antimicrobial dendrimers and polypeptides, peptidomimetics, and AMP-drug conjugates and consider recent developments in their chem. synthesis.
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    33. 33
      Büyükkiraz, E. M.; Kesmen, Z. Antimicrobial peptides (AMPs): A promising class of antimicrobial compounds. J. Appl. Microbiol. 2022, 132, 1573– 1596,  DOI: 10.1111/jam.15314
      [Crossref], [PubMed], Google Scholar
      There is no corresponding record for this reference.
    34. 34
      Lei, J.; Sun, L.; Huang, S.; Zhu, C.; Li, P.; He, J.; Mackey, V.; Coy, D. H.; He, Q. The antimicrobial peptides and their potential clinical applications. Am. J. Transl. Res. 2019, 11, 3919– 3931
      [PubMed], [CAS], Google Scholar
      34
      The antimicrobial peptides and their potential clinical applications
      Lei, Jun; Sun, Lichun; Huang, Siyu; Zhu, Chenhong; Li, Ping; He, Jun; Mackey, Vienna; Coy, David H.; He, Quanyong
      American Journal of Translational Research (2019), 11 (7), 3919-3931CODEN: AJTRA7; ISSN:1943-8141. (e-Century Publishing Corp.)
      Nowadays, the bacterial drug resistance leads to serious healthy problem worldwide due to the long-term use and the abuse of traditional antibiotics result in drug resistance of bacteria. Finding a new antibiotic is becoming more and more difficult. Antimicrobial peptides (AMPs) are the host defense peptides with most of them being the cationic (pos. charged) and amphiphilic (hydrophilic and hydrophobic) α-helical peptide mols. The membrane permeability is mostly recognized as the well-accepted mechanism to describe the action of cationic AMPs. These cationic AMPs can bind and interact with the neg. charged bacterial cell membranes, leading to the change of the electrochem. potential on bacterial cell membranes, inducing cell membrane damage and the permeation of larger mols. such as proteins, destroying cell morphol. and membranes and eventually resulting in cell death. These AMPs have been demonstrated to have their own advantages over the traditional antibiotics with a broad-spectrum of antimicrobial activities including anti-bacteria, anti-fungi, anti-viruses, and anti-cancers, and even overcome bacterial drug-resistance. The natural AMPs exist in a variety of organisms and are not stable with a short half-life, more or less toxic side effects, and particularly may have severe hemolytic activity. To open the clin. applications, it is necessary and important to develop the synthetic and long-lasting AMP analogs that overcome the disadvantages of their natural peptides and the potential problems for the drug candidates.
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    35. 35
      Tossi, A.; Scocchi, M.; Skerlavaj, B.; Gennaro, R. Identification and characterization of a primary antibacterial domain in CAP18, a lipopolysaccharide binding protein from rabbit leukocytes. FEBS Lett. 1994, 339, 108– 112,  DOI: 10.1016/0014-5793(94)80395-1
      [Crossref], [PubMed], [CAS], Google Scholar
      35
      Identification and characterization of a primary antibacterial domain in CAP18, a lipopolysaccharide binding protein from rabbit leukocytes
      Tossi, Alessandro; Scocchi, Marco; Skerlavaj, Barbara; Gennaro, Renato
      FEBS Letters (1994), 339 (1-2), 108-12CODEN: FEBLAL; ISSN:0014-5793.
      Secondary structure prediction studies on CAP18, a lipopolysaccharide binding protein from rabbit granulocytes, identified a highly cationic, 21-residue sequence with the tendency to adopt an amphipathic α-helical conformation, as obsd. in many antimicrobial peptides. The corresponding peptide was chem. synthesized and shown to exert a potent bactericidal activity against both Gram-neg. and Gram-pos. bacteria, and a rapid permeabilization of the inner membrane of Escherichia coli. Five analogs were synthesized to elucidate structure/activity relationships. It was found that helix disruption virtually eliminates antibacterial activity, while the degree of amphipathicity and the presence of an arom. residue greatly affect the kinetics of bacterial inner membrane permeabilization.
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    36. 36
      Tencza, S. B.; Creighton, D. J.; Yuan, T.; Vogel, H. J.; Montelaro, R. C.; Mietzner, T. A. Lentivirus-derived antimicrobial peptides: Increased potency by sequence engineering and dimerization. J. Antimicrob. Chemother. 1999, 44, 33– 41,  DOI: 10.1093/jac/44.1.33
      [Crossref], [PubMed], [CAS], Google Scholar
      36
      Lentivirus-derived antimicrobial peptides: increased potency by sequence engineering and dimerization
      Tencza, Sarah Burroughs; Creighton, Donald J.; Yuan, Tao; Vogel, Hans J.; Montelaro, Ronald C.; Mietzner, Timothy A.
      Journal of Antimicrobial Chemotherapy (1999), 44 (1), 33-41CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
      We have previously described a family of cationic amphipathic peptides derived from lentivirus envelope proteins that have properties similar to those of naturally occurring antimicrobial peptides. Here, we explored the effects of amino acid truncations and substitutions on the antimicrobial potency and selectivity of the prototype peptide, LLP1. Removal of seven residues from the C-terminus of LLP1 had little effect on potency, but abrogated hemolytic activity. Replacement of the two glutamic acid residues of LLP1 with arginine resulted in a peptide with greater bactericidal activity. We discovered that the cysteine-contg. peptides spontaneously formed disulfide-linked dimers, which were 16-fold more bactericidal to Staphylococcus aureus. Monomeric and dimeric LLP1 possessed similar alpha helical contents, indicating that disulfide formation did not alter the peptide's secondary structure. The dimerization strategy was applied to magainin 2, enhancing its bactericidal activity eight-fold. By optimizing all three properties of LLP1, a highly potent and selective peptide, named TL-1, was produced. This peptide is significantly more potent than LLP1 against Gram-pos. bacteria while maintaining high activity against Gram-neg. organisms and low activity against eukaryotic cells. In addn. to new antimicrobial peptides, these studies contribute useful information on which further peptide engineering efforts can be based.
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    37. 37
      Lau, Y. H.; De Andrade, P.; Wu, Y.; Spring, D. R. Peptide stapling techniques based on different macrocyclisation chemistries. Chem. Soc. Rev. 2015, 44, 91– 102,  DOI: 10.1039/c4cs00246f
      [Crossref], [PubMed], [CAS], Google Scholar
      37
      Peptide stapling techniques based on different macrocyclization chemistries
      Lau, Yu Heng; de Andrade, Peterson; Wu, Yuteng; Spring, David R.
      Chemical Society Reviews (2015), 44 (1), 91-102CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Peptide stapling is a strategy for constraining short peptides typically in an alpha-helical conformation. Stapling is carried out by covalently linking the side-chains of two amino acids, thereby forming a peptide macrocycle. There is an expanding repertoire of stapling techniques based on different macrocyclization chemistries. In this tutorial review, the authors categorize and analyze key examples of peptide stapling in terms of their synthesis and applicability to biol. systems.
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    38. 38
      Migoń, D.; Neubauer, D.; Kamysz, W. Hydrocarbon Stapled Antimicrobial Peptides. Protein J. 2018, 37, 2– 12,  DOI: 10.1007/s10930-018-9755-0
      [Crossref], [PubMed], [CAS], Google Scholar
      38
      Hydrocarbon Stapled Antimicrobial Peptides
      Migon, Dorian; Neubauer, Damian; Kamysz, Wojciech
      Protein Journal (2018), 37 (1), 2-12CODEN: PJROAH; ISSN:1572-3887. (Springer)
      A Review. Antimicrobial peptides are promising candidates for anti-infective pharmaceuticals. Unfortunately, because of their low proteolytic and chem. stability, their usage is generally narrowed down to topical formulations. Until now, numerous approaches to increase peptide stability have been proposed. One of them, peptide hydrocarbon stapling, a modification based on stabilizing peptide secondary structure with a side-chain covalent hydrocarbon bridge, have been successfully applied to many peptides. Moreover, constraining secondary structure of peptides have also been proven to increase their biol. activity. This review article describes studies on hydrocarbon stapled antimicrobial peptides with respect to improved drug-like properties.
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    39. 39
      Blackwell, H. E.; Grubbs, R. H. Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis. Angew. Chem., Int. Ed. 1998, 37, 3281– 3284,  DOI: 10.1002/(sici)1521-3773(19981217)37:23<3281::aid-anie3281>3.0.co;2-v
      [Crossref], [CAS], Google Scholar
      39
      Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis
      Blackwell, Helen E.; Grubbs, Robert H.
      Angewandte Chemie, International Edition (1998), 37 (23), 3281-3284CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
      Ring closing metathesis of acyclic peptide dienes Boc-Val-X-Leu-Aib-Val-X-Leu-OMe [I; Boc = Me3CO2C; X = Ser(CH2CH:CH2), Hse(CH2CH:CH2); Aib = NHCMe2CO], prepd. by std. solid-phase peptide chem., using olefin metathesis catalyst (PCy3)2Cl2Ru:CHPh gave 21- and 23-membered macrocyclic alkenes I in 85 and 90% yields, resp. Hydrogenation of II gave the corresponding alkane-bridged cyclopeptides III in 98% yield. Significant conformational change did not occur on cyclization of I to III, as evidenced by far-UV CD. A crystal structure of III (X = Hse) is reported.
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    40. 40
      Chapuis, H.; Slaninová, J.; Bednárová, L.; Monincová, L.; Buděšínský, M.; Čeřovský, V. Effect of hydrocarbon stapling on the properties of α-helical antimicrobial peptides isolated from the venom of hymenoptera. Amino Acids 2012, 43, 2047– 2058,  DOI: 10.1007/s00726-012-1283-1
      [Crossref], [PubMed], [CAS], Google Scholar
      40
      Effect of hydrocarbon stapling on the properties of α-helical antimicrobial peptides isolated from the venom of hymenoptera
      Chapuis, Hubert; Slaninova, Jirina; Bednarova, Lucie; Monincova, Lenka; Budesinsky, Milos; Cerovsky, Vaclav
      Amino Acids (2012), 43 (5), 2047-2058CODEN: AACIE6; ISSN:0939-4451. (SpringerWienNewYork)
      The impact of inserting hydrocarbon staples into short α-helical antimicrobial peptides lasioglossin III and melectin (antimicrobial peptides of wild bee venom) on their biol. and biophys. properties has been examd. The stapling was achieved by ring-closing olefin metathesis, either between two S-2-(4'-pentenyl) alanine residues (S 5) incorporated at i and i + 4 positions or between R-2-(7'-octenyl) alanine (R 8) and S 5 incorporated at the i and i + 7 positions, resp. We prepd. several lasioglossin III and melectin analogs with a single staple inserted into different positions within the peptide chains as well as analogs with double staples. The stapled peptides exhibited a remarkable increase in hemolytic activity, while their antimicrobial activities decreased. Some single stapled peptides showed a higher resistance against proteolytic degrdn. than native ones, while the double stapled analogs were substantially more resistant. The CD spectra of the singly stapled peptides measured in water showed only a slightly better propensity to form α-helical structure when compared to native peptides, whereas the doubly stapled analogs exhibited dramatically enhanced α-helicity.
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    41. 41
      Bird, G. H.; Madani, N.; Perry, A. F.; Princiotto, A. M.; Supko, J. G.; He, X.; Gavathiotis, E.; Sodroski, J. G.; Walensky, L. D. Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 14093– 14098,  DOI: 10.1073/pnas.1002713107
      [Crossref], [PubMed], [CAS], Google Scholar
      41
      Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic
      Bird, Gregory H.; Madani, Navid; Perry, Alisa F.; Princiotto, Amy M.; Supko, Jeffrey G.; He, Xiaoying; Gavathiotis, Evripidis; Sodroski, Joseph G.; Walensky, Loren D.
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (32), 14093-14098, S14093/1-S14093/8CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The pharmacol. utility of lengthy peptides can be hindered by loss of bioactive structure and rapid proteolysis, which limits bioavailability. For example, enfuvirtide (Fuzeon, T20, DP178), a 36-amino acid peptide that inhibits human immunodeficiency virus type 1 (HIV-1) infection by effectively targeting the viral fusion app., has been relegated to a salvage treatment option mostly due to poor in vivo stability and lack of oral bioavailability. To overcome the proteolytic shortcomings of long peptides as therapeutics, the authors examd. the biophys., biol., and pharmacol. impact of inserting all-hydrocarbon staples into an HIV-1 fusion inhibitor. The authors find that peptide double-stapling confers striking protease resistance that translates into markedly improved pharmacokinetic properties, including oral absorption. The authors detd. that the hydrocarbon staples create a proteolytic shield by combining reinforcement of overall α-helical structure, which slows the kinetics of proteolysis, with complete blockade of peptide cleavage at constrained sites in the immediate vicinity of the staple. Importantly, double-stapling also optimizes the antiviral activity of HIV-1 fusion peptides and the antiproteolytic feature extends to other therapeutic peptide templates, such as the diabetes drug exenatide (Byetta). Thus, hydrocarbon double-stapling may unlock the therapeutic potential of natural bioactive polypeptides by transforming them into structurally fortified agents with enhanced bioavailability.
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    42. 42
      Walensky, L. D.; Bird, G. H. Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress. J. Med. Chem. 2014, 57, 6275– 6288,  DOI: 10.1021/jm4011675
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      42
      Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress
      Walensky, Loren D.; Bird, Gregory H.
      Journal of Medicinal Chemistry (2014), 57 (15), 6275-6288CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Protein structure underlies essential biol. processes and provides a blueprint for mol. mimicry that drives drug discovery. Although small mols. represent the lion's share of agents that target proteins for therapeutic benefit, there remains no substitute for the natural properties of proteins and their peptide subunits in the majority of biol. contexts. The peptide α-helix represents a common structural motif that mediates communication between signaling proteins. Because peptides can lose their shape when taken out of context, developing chem. interventions to stabilize their bioactive structure remains an active area of research. The all-hydrocarbon staple has emerged as one such soln., conferring α-helical structure, protease resistance, cellular penetrance, and biol. activity upon successful incorporation of a series of design and application principles. Here, we describe our more than decade-long experience in developing stapled peptides as biomedical research tools and prototype therapeutics, highlighting lessons learned, pitfalls to avoid, and keys to success.
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    43. 43
      Mourtada, R.; Herce, H. D.; Yin, D. J.; Moroco, J. A.; Wales, T. E.; Engen, J. R.; Walensky, L. D. Design of Stapled Antimicrobial Peptides That Overcome Antibiotic Resistance and In Vivo Toxicity. Nat. Biotechnol. 2019, 37, 1186– 1197,  DOI: 10.1038/s41587-019-0222-z
      [Crossref], [PubMed], [CAS], Google Scholar
      43
      Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice
      Mourtada, Rida; Herce, Henry D.; Yin, Daniel J.; Moroco, Jamie A.; Wales, Thomas E.; Engen, John R.; Walensky, Loren D.
      Nature Biotechnology (2019), 37 (10), 1186-1197CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
      The clin. translation of cationic α-helical antimicrobial peptides (AMPs) has been hindered by structural instability, proteolytic degrdn. and in vivo toxicity from nonspecific membrane lysis. Although analyses of hydrophobic content and charge distribution have informed the design of synthetic AMPs with increased potency and reduced in vitro hemolysis, nonspecific membrane toxicity in vivo continues to impede AMP drug development. Here, we analyzed a 58-member library of stapled AMPs (StAMPs) based on magainin II and applied the insights from structure-function-toxicity measurements to devise an algorithm for the design of stable, protease-resistant, potent and nontoxic StAMP prototypes. We show that a lead double-stapled StAMP named Mag(i+4)1,15(A9K,B21A,N22K,S23K) can kill multidrug-resistant Gram-neg. pathogens, such as colistin-resistant Acinetobacter baumannii in a mouse peritonitis-sepsis model, without obsd. hemolysis or renal injury in murine toxicity studies. Inputting the amino acid sequences alone, we further generated membrane-selective StAMPs of pleurocidin, CAP18 and esculentin, highlighting the generalizability of our design platform.
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    44. 44
      Libardo, M. D. J.; Nagella, S.; Lugo, A.; Pierce, S.; Angeles-Boza, A. M. Copper-binding tripeptide motif increases potency of the antimicrobial peptide Anoplin via Reactive Oxygen Species generation. Biochem. Biophys. Res. Commun. 2015, 456, 446– 451,  DOI: 10.1016/j.bbrc.2014.11.104
      [Crossref], [PubMed], [CAS], Google Scholar
      44
      Copper-binding tripeptide motif increases potency of the antimicrobial peptide Anoplin via Reactive Oxygen Species generation
      Libardo, M. Daben J.; Nagella, Sai; Lugo, Andrea; Pierce, Scott; Angeles-Boza, Alfredo M.
      Biochemical and Biophysical Research Communications (2015), 456 (1), 446-451CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
      Antimicrobial peptides (AMPs) are broad spectrum antimicrobial agents that act through diverse mechanisms, this characteristic makes them suitable starting points for development of novel classes of antibiotics. We have previously reported the increase in activity of AMPs upon addn. of the Amino Terminal Copper and Nickel (ATCUN) Binding Unit. Herein we synthesized the membrane active peptide, Anoplin and two ATCUN-Anoplin derivs. and show that the increase in activity is indeed due to the ROS formation by the CuII-ATCUN complex. We found that the ATCUN-Anoplin peptides were up to four times more potent compared to Anoplin alone against std. test bacteria. We studied membrane disruption, and cellular localization and found that addn. of the ATCUN motif did not lead to a difference in these properties. When helical content was calcd., we obsd. that ATCUN-Anoplin had a lower helical compn. We found that ATCUN-Anoplin are able to oxidatively damage lipids in the bacterial membrane and that their activity trails the rate at which ROS is formed by the CuII-ATCUN complexes alone. This study shows that addn. of a metal binding tripeptide motif is a simple strategy to increase potency of AMPs by conferring a secondary action.
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    45. 45
      Zhong, C.; Gou, S.; Liu, T.; Zhu, Y.; Zhu, N.; Liu, H.; Zhang, Y.; Xie, J.; Guo, X.; Ni, J. Study on the effects of different dimerization positions on biological activity of partial d-Amino acid substitution analogues of Anoplin. Microb. Pathog. 2020, 139, 103871,  DOI: 10.1016/j.micpath.2019.103871
      [Crossref], [PubMed], [CAS], Google Scholar
      45
      Study on the effects of different dimerization positions on biological activity of partial D-Amino acid substitution analogues of Anoplin
      Zhong, Chao; Gou, Sanhu; Liu, Tianqi; Zhu, Yuewen; Zhu, Ningyi; Liu, Hui; Zhang, Yun; Xie, Junqiu; Guo, Xiaomin; Ni, Jingman
      Microbial Pathogenesis (2020), 139 (), 103871CODEN: MIPAEV; ISSN:0882-4010. (Elsevier Ltd.)
      Antimicrobial peptides have recently attracted much attention due to their broad-spectrum antimicrobial activity, rapid microbial effects, and minimal tendency toward resistance development. In this study, a series of new C-C terminals and C-N terminals dimer peptides were designed and synthesized by intermol. dimerization of the partial D-amino acid substitution analogs of Anoplin, and the effects of different dimerization positions on biol. activity were researched. The antimicrobial activity and stability of the new C-C terminals and C-N terminals dimer peptides were significantly improved compared with their parent peptide Anoplin. They displayed no obvious hemolytic activity and lower cytotoxicity, with a higher therapeutic index. Furthermore, the new dimer peptides not only enabled to rapidly disrupt bacterial membrane and damage its integrity which was different from conventional antibiotics but also penetrated bacterial membrane into binding to intracellular genomic DNA. More importantly, the new dimer peptides showed excellent antimicrobial activity against multidrug-resistant strains isolated from clinics in contrast to conventional antibiotics with low tendency to develop the bacterial resistance, besides they exhibited better anti-biofilm activity than antibiotic Rifampicin. Interestingly, the C-N terminals dimer peptides were superior to C-C terminals ones in antimicrobial and anti-biofilm activity, therapeutic index, outer membrane permeability, and DNA binding ability, whereas there were no noteworthy effects in different dimerization positions on stability. Thus, these data suggested that dimerization in different positions represented a potent strategy to develop novel antimicrobial agents for fighting against increasing bacterial resistance.
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    46. 46
      Wu, Y.; Lu, D.; Jiang, Y.; Jin, J.; Liu, S.; Chen, L.; Zhang, H.; Zhou, Y.; Chen, H.; Nagle, D. G.; Luan, X.; Zhang, W. Stapled Wasp Venom-Derived Oncolytic Peptides with Side Chains Induce Rapid Membrane Lysis and Prolonged Immune Responses in Melanoma. J. Med. Chem. 2021, 64, 5802– 5815,  DOI: 10.1021/acs.jmedchem.0c02237
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      46
      Stapled Wasp Venom-Derived Oncolytic Peptides with Side Chains Induce Rapid Membrane Lysis and Prolonged Immune Responses in Melanoma
      Wu, Ye; Lu, Dong; Jiang, Yixin; Jin, Jinmei; Liu, Sanhong; Chen, Lili; Zhang, Hong; Zhou, Yudong; Chen, Hongzhuan; Nagle, Dale G.; Luan, Xin; Zhang, Weidong
      Journal of Medicinal Chemistry (2021), 64 (9), 5802-5815CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Peptide stapling chem. represents an attractive strategy to promote the clin. translation of protein epitope mimetics, but its use has not been applied to natural cytotoxic peptides (NCPs) to produce new oncolytic peptides. Based on a wasp venom peptide, a series of stapled anoplin peptides (StAnos) were prepd. The optimized stapled Ano-3/3s were shown to be protease-resistant and exerted superior tumor cell-selective cytotoxicity by rapid membrane disruption. In addn., Ano-3/3s induced tumor ablation in mice through the direct oncolytic effect and subsequent stimulation of immunogenic cell death. This synergistic oncolytic-immunotherapy effect is more remarkable on melanoma than on triple-neg. breast cancer in vivo. The efficacies exerted by Ano-3/3s on melanoma were further characterized by CD8+ T cell infiltration, and the addn. of anti-CD8 antibodies diminished the long-term antitumor effects. In summary, these results support stapled peptide chem. as an advantageous method to enhance the NCP potency for oncolytic therapy.
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    47. 47
      Wang, Y.; Chen, J.; Zheng, X.; Yang, X.; Ma, P.; Cai, Y.; Zhang, B.; Chen, Y. Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity. J. Pept. Sci. 2014, 20, 945– 951,  DOI: 10.1002/psc.2705
      [Crossref], [PubMed], [CAS], Google Scholar
      47
      Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity
      Wang, Yang; Chen, Jianbo; Zheng, Xin; Yang, Xiaoli; Ma, Panpan; Cai, Ying; Zhang, Bangzhi; Chen, Yuan
      Journal of Peptide Science (2014), 20 (12), 945-951CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
      Currently, novel antibiotics are urgently required to combat the emergence of drug-resistant bacteria. Antimicrobial peptides with membrane-lytic mechanism of action have attracted considerable interest. Anoplin, a natural α-helical amphiphilic antimicrobial peptide, is an ideal research template because of its short sequence. In this study, we designed and synthesized a group of analogs of anoplin. Among these analogs, anoplin-4 composed of D-amino acids displayed the highest antimicrobial activity due to increased charge, hydrophobicity, and amphiphilicity. Gratifyingly, anoplin-4 showed low toxicity to host cells, indicating high bacterial selectivity. Furthermore, the mortality rate of mice infected with Escherichia coli was significantly reduced by anoplin-4 treatment relative to anoplin. In conclusion, anoplin-4 is a novel anoplin analog with high antimicrobial activity and enzymic stability, which may represent a potent agent for the treatment of infection. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.
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    48. 48
      Wojciechowska, M.; Miszkiewicz, J.; Trylska, J. Conformational Changes of Anoplin, W-MreB1–9, and (KFF)3K Peptides near the Membranes. Int. J. Mol. Sci. 2020, 21, 9672,  DOI: 10.3390/ijms21249672
      [Crossref], [PubMed], [CAS], Google Scholar
      48
      Conformational changes of anoplin, W-MreB1-9, and (KFF)3K peptides near the membranes
      Wojciechowska, Monika; Miszkiewicz, Joanna; Trylska, Joanna
      International Journal of Molecular Sciences (2020), 21 (24), 9672CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      Many peptides interact with biol. membranes, but elucidating these interactions is challenging because cellular membranes are complex and peptides are structurally flexible. To contribute to understanding how the membrane-active peptides behave near the membranes, we investigated peptide structural changes in different lipid surroundings. We focused on two antimicrobial peptides, anoplin and W-MreB1-9, and one cell-penetrating peptide, (KFF)3K. Firstly, by using CD spectroscopy, we detd. the secondary structures of these peptides when interacting with micelles, liposomes, E. coli lipopolysaccharides, and live E. coli bacteria. The peptides were disordered in the buffer, but anoplin and W-MreB1-9 displayed lipid-induced helicity. Yet, structural changes of the peptide depended on the compn. and concn. of the membranes. Secondly, we quantified the destructive activity of peptides against liposomes by monitoring the release of a fluorescent dye (calcein) from the liposomes treated with peptides. We obsd. that only for anoplin and W-MreB1-9 calcein leakage from liposomes depended on the peptide concn. Thirdly, bacterial growth inhibition assays showed that peptide conformational changes, evoked by the lipid environments, do not directly correlate with the antimicrobial activity of the peptides. However, understanding the relation between peptide structural properties, mechanisms of membrane disruption, and their biol. activities can guide the design of membrane-active peptides.
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    49. 49
      Wojciechowska, M.; Macyszyn, J.; Miszkiewicz, J.; Grzela, R.; Trylska, J. Stapled Anoplin as an Antibacterial Agent. Front. Microbiol. 2021, 12, 772038,  DOI: 10.3389/fmicb.2021.772038
      [Crossref], [PubMed], [CAS], Google Scholar
      49
      Stapled Anoplin as an Antibacterial Agent
      Wojciechowska Monika; Macyszyn Julia; Miszkiewicz Joanna; Grzela Renata; Trylska Joanna; Miszkiewicz Joanna; Grzela Renata
      Frontiers in microbiology (2021), 12 (), 772038 ISSN:1664-302X.
      Anoplin is a linear 10-amino acid amphipathic peptide (Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-NH2 ) derived from the venom sac of the solitary wasp. It has broad antimicrobial activity, including an antibacterial one. However, the inhibition of bacterial growth requires several dozen micromolar concentrations of this peptide. Anoplin is positively charged and directly interacts with anionic biological membranes forming an α-helix that disrupts the lipid bilayer. To improve the bactericidal properties of anoplin by stabilizing its helical structure, we designed and synthesized its analogs with hydrocarbon staples. The staple was introduced at two locations resulting in different charges and amphipathicity of the analogs. Circular dichroism studies showed that all modified anoplins adopted an α-helical conformation, both in the buffer and in the presence of membrane mimics. As the helicity of the stapled anoplins increased, their stability in trypsin solution improved. Using the propidium iodide uptake assay in Escherichia coli and Staphylococcus aureus, we confirmed the bacterial membrane disruption by the stapled anoplins. Next, we tested the antimicrobial activity of peptides on a range of Gram-negative and Gram-positive bacteria. Finally, we evaluated peptide hemolytic activity on sheep erythrocytes and cytotoxicity on human embryonic kidney 293 cells. All analogs showed higher antimicrobial activity than unmodified anoplin. Depending on the position of the staple, the peptides were more effective either against Gram-negative or Gram-positive bacteria. Anoplin[5-9], with a lower positive charge and increased hydrophobicity, had higher activity against Gram-positive bacteria but also showed hemolytic and destructive effects on eukaryotic cells. Contrary, anoplin[2-6] with a similar charge and amphipathicity as natural anoplin effectively killed Gram-negative bacteria, also pathogenic drug-resistant strains, without being hemolytic and toxic to eukaryotic cells. Our results showed that anoplin charge, amphipathicity, and location of hydrophobic residues affect the peptide destructive activity on the cell wall, and thus, its antibacterial activity. This means that by manipulating the charge and position of the staple in the sequence, one can manipulate the antimicrobial activity.
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    50. 50
      Sahariah, P.; Sørensen, K. K.; Hjálmarsdóttir, M. A.; Sigurjónsson, Ó. E.; Jensen, K. J.; Másson, M.; Thygesen, M. B. Antimicrobial peptide shows enhanced activity and reduced toxicity upon grafting to chitosan polymers. Chem. Commun. 2015, 51, 11611– 11614,  DOI: 10.1039/c5cc04010h
      [Crossref], [PubMed], [CAS], Google Scholar
      50
      Antimicrobial peptide shows enhanced activity and reduced toxicity upon grafting to chitosan polymers
      Sahariah, Priyanka; Soerensen, Kasper K.; Hjalmarsdottir, Martha A.; Sigurjonsson, Olafur E.; Jensen, Knud J.; Masson, Mar; Thygesen, Mikkel B.
      Chemical Communications (Cambridge, United Kingdom) (2015), 51 (58), 11611-11614CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Here we report that grafting of a short antimicrobial peptide, anoplin, to chitosan polymers is a strategy for abolishing the hemolytic propensity, and at the same time increasing the activity of the parent peptide. Anoplin-chitosan conjugates were synthesized by CuAAC reaction of multiple peptides through 2-azidoacetyl groups on chitosan.
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    51. 51
      Konno, K.; Hisada, M.; Fontana, R.; Lorenzi, C. C. B.; Naoki, H.; Itagaki, Y.; Miwa, A.; Kawai, N.; Nakata, Y.; Yasuhara, T.; Ruggiero Neto, J.; de Azevedo, W. F.; Palma, M. S.; Nakajima, T. Anoplin, a novel antimicrobial peptide from the venom of the solitary wasp Anoplius samariensis. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 2001, 1550, 70– 80,  DOI: 10.1016/s0167-4838(01)00271-0
      [Crossref], [PubMed], [CAS], Google Scholar
      51
      Anoplin, a novel antimicrobial peptide from the venom of the solitary wasp Anoplius samariensis
      Konno, Katsuhiro; Hisada, Miki; Fontana, Renato; Lorenzi, Carla C. B.; Naoki, Hideo; Itagaki, Yasuhiro; Miwa, Akiko; Kawai, Nobufumi; Nakata, Yoshihiro; Yasuhara, Tadashi; Ruggiero Neto, Joao; de Azevedo, Walter F.; Palma, Mario S.; Nakajima, Terumi
      Biochimica et Biophysica Acta, Protein Structure and Molecular Enzymology (2001), 1550 (1), 70-80CODEN: BBAEDZ; ISSN:0167-4838. (Elsevier B.V.)
      A novel antimicrobial peptide, anoplin, was purified from the venom of the solitary wasp Anoplius samariensis. The sequence was mostly analyzed by mass spectrometry, which was corroborated by solid-phase synthesis. Anoplin, composed of 10 amino acid residues, Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-NH2, has a high homol. to crabrolin and mastoparan-X, the mast cell degranulating peptides from social wasp venoms, and, therefore, can be predicted to adopt an amphipathic α-helix secondary structure. In fact, the CD spectra of anoplin in the presence of trifluoroethanol or SDS showed a high content, up to 55%, of the α-helical conformation. A modeling study of anoplin based on its homol. to mastoparan-X supported the CD results. Biol. evaluation using the synthetic peptide revealed that this peptide exhibited potent activity in stimulating degranulation from rat peritoneal mast cells and broad-spectrum antimicrobial activity against both Gram-pos. and Gram-neg. bacteria. Therefore, this is the first antimicrobial component to be found in the solitary wasp venom and it may play a key role in preventing potential infection by microorganisms during prey consumption by their larvae. Moreover, this peptide is the smallest among the linear α-helical antimicrobial peptides hitherto found in nature, which is advantageous for chem. manipulation and medical application.
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    52. 52
      Klahn, P.; Brönstrup, M. Bifunctional antimicrobial conjugates and hybrid antimicrobials. Nat. Prod. Rep. 2017, 34, 832– 885,  DOI: 10.1039/c7np00006e
      [Crossref], [PubMed], [CAS], Google Scholar
      52
      Bifunctional antimicrobial conjugates and hybrid antimicrobials
      Klahn, P.; Broenstrup, M.
      Natural Product Reports (2017), 34 (7), 832-885CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
      A review. Novel antimicrobial drugs are continuously needed to counteract bacterial resistance development. An innovative mol. design strategy for novel antibiotic drugs is based on the hybridization of an antibiotic with a second functional entity. Such conjugates can be grouped into two major categories. In the first category (antimicrobial hybrids), both functional elements of the hybrid exert antimicrobial activity. Due to the dual targeting, resistance development can be significantly impaired, the pharmacokinetic properties can be superior compared to combination therapies with the single antibiotics, and the antibacterial potency is often enhanced in a synergistic manner. In the second category (antimicrobial conjugates), one functional moiety controls the accumulation of the other part of the conjugate, e.g. by mediating an active transport into the bacterial cell or blocking the efflux. This approach is mostly applied to translocate compds. across the cell envelope of Gram-neg. bacteria through membrane-embedded transporters (e.g. siderophore transporters) that provide nutrition and signalling compds. to the cell. Such 'Trojan Horse' approaches can expand the antibacterial activity of compds. against Gram-neg. pathogens, or offer new options for natural products that could not be developed as standalone antibiotics, e.g. due to their toxicity.
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    53. 53
      Deshayes, S.; Xian, W.; Schmidt, N. W.; Kordbacheh, S.; Lieng, J.; Wang, J.; Zarmer, S.; Germain, S. S.; Voyen, L.; Thulin, J.; Wong, G. C. L.; Kasko, A. M. Designing Hybrid Antibiotic Peptide Conjugates to Cross Bacterial Membranes. Bioconjugate Chem. 2017, 28, 793– 804,  DOI: 10.1021/acs.bioconjchem.6b00725
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      53
      Designing Hybrid Antibiotic Peptide Conjugates To Cross Bacterial Membranes
      Deshayes, Stephanie; Xian, Wujing; Schmidt, Nathan W.; Kordbacheh, Shadi; Lieng, Juelline; Wang, Jennifer; Zarmer, Sandra; Germain, Samantha St.; Voyen, Laura; Thulin, Julia; Wong, Gerard C. L.; Kasko, Andrea M.
      Bioconjugate Chemistry (2017), 28 (3), 793-804CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      We design hybrid antibiotic peptide conjugates that can permeate membranes. Integration of multiple components with different functions into a single mol. is often problematic, due to competing chem. requirements for different functions and to mutual interference. By examg. the structure of antimicrobial peptides, we show that it is possible to design and synthesize membrane active antibiotic peptide conjugates that synergistically combine multiple forms of antimicrobial activity, resulting in unusually strong activity against persistent bacterial strains.
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    54. 54
      Fosso, M. Y.; Li, Y.; Garneau-Tsodikova, S. New trends in the use of aminoglycosides. MedChemComm 2014, 5, 1075– 1091,  DOI: 10.1039/c4md00163j
      [Crossref], [PubMed], [CAS], Google Scholar
      54
      New trends in the use of aminoglycosides
      Fosso, Marina Y.; Li, Yijia; Garneau-Tsodikova, Sylvie
      MedChemComm (2014), 5 (8), 1075-1091CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
      A review. Despite their inherent toxicity and the acquired bacterial resistance that continuously threaten their long-term clin. use, aminoglycosides (AGs) still remain valuable components of the antibiotic armamentarium. Recent literature shows that the AGs' role has been further expanded as multi-tasking players in different areas of study. This review aims at presenting some of the new trends obsd. in the use of AGs in the past decade, along with the current understanding of their mechanisms of action in various bacterial and eukaryotic cellular processes.
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    55. 55
      Chandrika, N. T.; Garneau-Tsodikova, S. A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides. MedChemComm 2016, 7, 50– 68,  DOI: 10.1039/c5md00453e
      [Crossref], [PubMed], [CAS], Google Scholar
      55
      A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides
      Chandrika, Nishad Thamban; Garneau-Tsodikova, Sylvie
      MedChemComm (2016), 7 (1), 50-68CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
      Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-neg. and Gram-pos. bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) assocd. with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concn. by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011-2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.
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    56. 56
      Bera, S.; Zhanel, G. G.; Schweizer, F. Antibacterial activities of aminoglycoside antibiotics-derived cationic amphiphiles. Polyol-modified neomycin B-Kanamycin A-Amikacin-and Neamine-based amphiphiles with potent broad spectrum antibacterial activity. J. Med. Chem. 2010, 53, 3626– 3631,  DOI: 10.1021/jm1000437
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      56
      Antibacterial activities of aminoglycoside antibiotic-derived cationic amphiphiles: Polyol-modified neomycin B-, kanamycin A-, amikacin-, and neamine-based amphiphiles with potent broad spectrum antibacterial activity
      Bera, Smritilekha; Zhanel, George G.; Schweizer, Frank
      Journal of Medicinal Chemistry (2010), 53 (9), 3626-3631CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Cationic amphiphiles contg. multiple pos. charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. The authors have prepd. a novel class of cationic amphiphiles termed aminoglycoside antibiotics-derived amphiphiles in which the polyol scaffold of the aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. The results show that the nature of the polyol modification as well as the nature of the aminoglycoside antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles contg. unsubstituted arom. rings. These analogs exhibit up to 256-fold enhanced antibacterial activity against resistant strains when compared to neomycin B while retaining most of their activity against neomycin B-susceptible strains.
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    57. 57
      Neumann, W.; Nolan, E. M. Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics. J. Biol. Inorg. Chem. 2018, 23, 1025– 1036,  DOI: 10.1007/s00775-018-1588-y
      [Crossref], [PubMed], [CAS], Google Scholar
      57
      Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics
      Neumann, Wilma; Nolan, Elizabeth M.
      JBIC, Journal of Biological Inorganic Chemistry (2018), 23 (7), 1025-1036CODEN: JJBCFA; ISSN:0949-8257. (Springer)
      Abstr.: Bacterial iron uptake machinery can be hijacked for the targeted delivery of antibiotics into pathogens by attaching antibiotics to siderophores, iron chelators that are employed by bacteria to obtain this essential nutrient. We synthesized and evaluated Ent-SS-Cipro, a siderophore-antibiotic conjugate comprised of the triscatecholate siderophore enterobactin and the fluoroquinolone antibiotic ciprofloxacin that contains a self-immolative disulfide linker. This linker is designed to be cleaved after uptake into the reducing environment of the bacterial cytoplasm. We show that the disulfide bond of Ent-SS-Cipro is cleaved by reducing agents, including the cellular reductant glutathione, which results in release of the unmodified fluoroquinolone antibiotic. Antibacterial activity assays against a panel of Escherichia coli show that Ent-SS-Cipro exhibits activity against some, but not all, E. coli. This work informs the design of siderophore-antibiotic conjugates, particularly those carrying antibiotics with cytoplasmic targets that require release after uptake into bacterial cells, and indicates that disulfide linkers may not be generally applicable for conjugation strategies of antibiotics.
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    58. 58
      Wierzba, A.; Wojciechowska, M.; Trylska, J.; Gryko, D. Vitamin B12 Suitably Tailored for Disulfide-Based Conjugation. Bioconjugate Chem. 2016, 27, 189– 197,  DOI: 10.1021/acs.bioconjchem.5b00599
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      58
      Vitamin B12 Suitably Tailored for Disulfide-Based Conjugation
      Wierzba, Aleksandra; Wojciechowska, Monika; Trylska, Joanna; Gryko, Dorota
      Bioconjugate Chemistry (2016), 27 (1), 189-197CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Vitamin B12 has been proposed to be a natural vector for the in vivo delivery of biol. active compds. Most synthetic methodologies leading to vitamin B12 conjugates involve functionalization at the 5' position via either carbamate-based linkages or using copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC), resulting in stable conjugates that are not cleaved within the cell. We have developed a novel vitamin B12 deriv. suitably tailored for disulfide-based conjugation that can undergo cleavage in the presence of glutathione, the most abundant thiol in mammalian cells. This active compd. is simple to prep. and allows for the direct disulfide-based attachment of therapeutic cargos.
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    59. 59
      Równicki, M.; Wojciechowska, M.; Wierzba, A. J.; Czarnecki, J.; Bartosik, D.; Gryko, D.; Trylska, J. Vitamin B12 as a carrier of peptide nucleic acid (PNA) into bacterial cells. Sci. Rep. 2017, 7, 7644– 7711,  DOI: 10.1038/s41598-017-08032-8
      [Crossref], [PubMed], [CAS], Google Scholar
      59
      Vitamin B12 as a carrier of peptide nucleic acid (PNA) into bacterial cells
      Rownicki Marcin; Rownicki Marcin; Wojciechowska Monika; Trylska Joanna; Wierzba Aleksandra J; Gryko Dorota; Czarnecki Jakub; Bartosik Dariusz
      Scientific reports (2017), 7 (1), 7644 ISSN:.
      Short modified oligonucleotides targeted at bacterial DNA or RNA could serve as antibacterial agents provided that they are efficiently taken up by bacterial cells. However, the uptake of such oligonucleotides is hindered by the bacterial cell wall. To overcome this problem, oligomers have been attached to cell-penetrating peptides, but the efficiency of delivery remains poor. Thus, we have investigated the ability of vitamin B12 to transport peptide nucleic acid (PNA) oligomers into cells of Escherichia coli and Salmonella Typhimurium. Vitamin B12 was covalently linked to a PNA oligomer targeted at the mRNA of a reporter gene expressing Red Fluorescent Protein. Cu-catalyzed 1,3-dipolar cycloaddition was employed for the synthesis of PNA-vitamin B12 conjugates; namely the vitamin B12 azide was reacted with PNA possessing the terminal alkyne group. Different types of linkers and spacers between vitamin B12 and PNA were tested, including a disulfide bond. We found that vitamin B12 transports antisense PNA into E. coli cells more efficiently than the most widely used cell-penetrating peptide (KFF)3K. We also determined that the structure of the linker impacts the antisense effect. The results of this study provide the foundation for developing vitamin B12 as a carrier of PNA oligonucleotides into bacterial cells.
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    60. 60
      Gautier, R.; Douguet, D.; Antonny, B.; Drin, G. HELIQUEST: A web server to screen sequences with specific α-helical properties. Bioinformatics 2008, 24, 2101– 2102,  DOI: 10.1093/bioinformatics/btn392
      [Crossref], [PubMed], [CAS], Google Scholar
      60
      HELIQUEST: a web server to screen sequences with specific α-helical properties
      Gautier, Romain; Douguet, Dominique; Antonny, Bruno; Drin, Guillaume
      Bioinformatics (2008), 24 (18), 2101-2102CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
      Summary: HELIQUEST calcs. the physicochem. properties and amino acid compn. of an α-helix and screens databases to identify protein segments possessing similar features. This server is also dedicated to mutating helixes manually or automatically by genetic algorithm to design analogs of defined features. Availability: http://heliquest.ipmc.cnrs.fr.
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    61. 61
      Hull, R.; Klinger, J. D.; Moody, E. E. M. Isolation and characterization of mutants of Escherichia coli K12 resistant to the new aminoglycoside antibiotic, amikacin. J. Gen. Microbiol. 1976, 94, 389– 394,  DOI: 10.1099/00221287-94-2-389
      [Crossref], [PubMed], [CAS], Google Scholar
      61
      Isolation and characterization of mutants of Escherichia coli K12 resistant to the new aminoglycoside antibiotic, amikacin
      Hull, R.; Klinger, J. D.; Moody, E. E. M.
      Journal of General Microbiology (1976), 94 (2), 389-94CODEN: JGMIAN; ISSN:0022-1287.
      Spontaneous mutants of Escherichia coli K12 were resistant to amikacin and simultaneously acquired cross-resistance to kanamycin, gentamicin, and neomycin, but not to streptomycin or spectinomycin. The sensitivity of the mutants to ampicillin, tetracycline, and polymyxin was not affected. The genetic locus for ribosomal resistance to amikacin was linked to the strA gene and was located distal to spcA with respect to aroE.
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    62. 62
      Jiang, L.; Watkins, D.; Jin, Y.; Gong, C.; King, A.; Washington, A. Z.; Green, K. D.; Garneau-Tsodikova, S.; Oyelere, A. K.; Arya, D. P. Rapid synthesis, RNA binding, and antibacterial screening of a peptidic-aminosugar (PA) library. ACS Chem. Biol. 2015, 10, 1278– 1289,  DOI: 10.1021/cb5010367
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      62
      Rapid Synthesis, RNA Binding, and Antibacterial Screening of a Peptidic-Aminosugar (PA) Library
      Jiang, Liuwei; Watkins, Derrick; Jin, Yi; Gong, Changjun; King, Ada; Washington, Arren Z.; Green, Keith D.; Garneau-Tsodikova, Sylvie; Oyelere, Adegboyega K.; Arya, Dev P.
      ACS Chemical Biology (2015), 10 (5), 1278-1289CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      A 215-member mono- and diamino acid peptidic-aminosugar (PA) library, with neomycin as the model aminosugar, was systematically and rapidly synthesized via solid-phase synthesis. Antibacterial activities of the PA library, on 13 bacterial strains (seven Gram-pos. and six Gram-neg. bacterial strains), and binding affinities of the PA library for a 27-base model of the bacterial 16S ribosomal A-site RNA were evaluated using high-throughput screening. The results of the two assays were correlated using Ribosomal Binding-Bacterial Inhibition Plot (RB-BIP) anal. to provide structure-activity relationship (SAR) information. In this work, the authors have identified PAs that can discriminate the E. coli A-site from the human A-site by up to a 28-fold difference in binding affinity. Aminoglycoside-modifying enzyme activity studies indicate that APH(2'')-Ia showed nearly complete removal of activity with a no. of PAs. The synthesis of the compd. library and screening can both be performed rapidly, allowing for an iterative process of aminoglycoside synthesis and screening of PA libraries for optimal binding and antibacterial activity for lead identification.
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    63. 63
      Fair, R. J.; Hensler, M. E.; Thienphrapa, W.; Dam, Q. N.; Nizet, V.; Tor, Y. Selectively Guanidinylated Aminoglycosides as Antibiotics. ChemMedChem 2012, 7, 1237– 1244,  DOI: 10.1002/cmdc.201200150
      [Crossref], [PubMed], [CAS], Google Scholar
      63
      Selectively guanidinylated aminoglycosides as antibiotics
      Fair, Richard J.; Hensler, Mary E.; Thienphrapa, Wdee; Dam, Quang N.; Nizet, Victor; Tor, Yitzhak
      ChemMedChem (2012), 7 (7), 1237-1244, S1237/1-S1237/26CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The emergence of virulent, drug-resistant bacterial strains coupled with a minimal output of new pharmaceutical agents to combat them makes this a crit. time for antibacterial research. Aminoglycosides are a well studied, highly potent class of naturally occurring antibiotics with scaffolds amenable to modification, and therefore, they provide an excellent starting point for the development of semisynthetic, next-generation compds. To explore the potential of this approach, the authors synthesized a small library of aminoglycoside derivs. selectively and minimally modified at one or two positions with a guanidine group replacing the corresponding amine or hydroxy functionality. Most guanidino-aminoglycosides showed increased affinity for the ribosomal decoding rRNA site, the cognate biol. target of the natural products, when compared with their parent antibiotics, as measured by an in vitro fluorescence resonance energy transfer (FRET) A-site binding assay. Addnl., certain analogs showed improved min. inhibitory concn. (MIC) values against resistant bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An amikacin deriv. holds particular promise with activity greater than or equal to the parent antibiotic in the majority of bacterial strains tested.
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    64. 64
      Spears, R. J.; McMahon, C.; Chudasama, V. Cysteine protecting groups: Applications in peptide and protein science. Chem. Soc. Rev. 2021, 50, 11098– 11155,  DOI: 10.1039/d1cs00271f
      [Crossref], [PubMed], [CAS], Google Scholar
      64
      Cysteine protecting groups: applications in peptide and protein science
      Spears, Richard J.; McMahon, Cliona; Chudasama, Vijay
      Chemical Society Reviews (2021), 50 (19), 11098-11155CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Protecting group chem. for the cysteine thiol group has enabled a vast array of peptide and protein chem. over the last several decades. Increasingly sophisticated strategies for the protection, and subsequent deprotection, of cysteine have been developed, facilitating synthesis of complex disulfide-rich peptides, semisynthesis of proteins, and peptide/protein labeling in vitro and in vivo. In this review, we analyze and discuss the 60+ individual protecting groups reported for cysteine, highlighting their applications in peptide synthesis and protein science.
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    65. 65
      Westermann, B.; Dörner, S.; Brauch, S.; Schaks, A.; Heinke, R.; Stark, S.; Van Delft, F. L.; Van Berkel, S. S. CuAAC-mediated diversification of aminoglycoside-arginine conjugate mimics by non-reducing di- and trisaccharides. Carbohydr. Res. 2013, 371, 61– 67,  DOI: 10.1016/j.carres.2013.02.003
      [Crossref], [PubMed], [CAS], Google Scholar
      65
      CuAAC-mediated diversification of aminoglycoside-arginine conjugate mimics by non-reducing disaccharide and trisaccharides
      Westermann, Bernhard; Doerner, Simon; Brauch, Sebastian; Schaks, Angela; Heinke, Ramona; Stark, Sebastian; van Delft, Floris L.; van Berkel, Sander S.
      Carbohydrate Research (2013), 371 (), 61-67CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
      Di- and triguanidinylation of trehalose, sucrose, and melizitose has been achieved via a Huisgen-cycloaddn. approach. They can serve as aminoglycoside-arginine conjugate mimics, which has been demonstrated by their biol. profiles in assays against Bacillus subtilis. For comparative studies, tetra-guanidinylated neamine and kanamycin derivs. have also been synthesized and evaluated.
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    66. 66
      Kobayashi, K.; Taguchi, A.; Cui, Y.; Shida, H.; Muguruma, K.; Takayama, K.; Taniguchi, A.; Hayashi, Y. “On-Resin” Disulfide Peptide Synthesis with Methyl 3-Nitro-2-pyridinesulfenate. Eur. J. Org. Chem. 2021, 2021, 956– 963,  DOI: 10.1002/ejoc.202001517
      [Crossref], [CAS], Google Scholar
      66
      "On-resin" disulfide peptide synthesis with methyl 3-nitro-2-pyridinesulfenate
      Kobayashi, Kiyotaka; Taguchi, Akihiro; Cui, Yan; Shida, Hayate; Muguruma, Kyohei; Takayama, Kentaro; Taniguchi, Atsuhiko; Hayashi, Yoshio
      European Journal of Organic Chemistry (2021), 2021 (6), 956-963CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      New methodologies for the construction of full peptide structures with all disulfide bonds on the resin are attractive for the development of solid phase peptide synthesis. Detailed reaction conditions for the on-resin disulfide bond formation have been investigated using a mild and chem. stable oxidizing reagent, Me 3-nitro-2-pyridinesulfenate (Npys-OMe). Monocyclic oxytocin, MCH and bicyclic α-conotoxin ImI were synthesized in both semi-automated and full-automated protocols. It was found that on-resin intramol. disulfide bond formation with Npys-OMe proceeds with the minimal formation of peptide oligomers by adopting a solvent system with 0.4 M LiCl/DMF. Crude peptides with complete disulfide bond patterns can be obtained in high purity using both protocols. This minimized the RP-HPLC purifn. step and the desired peptides were obtained with better yields. To our knowledge, this is the first fully automated construction of a bicyclic disulfide peptide on resin with more than 50% purity in Fmoc-based SPPS. These results suggest that Npys-OMe is a useful reagent for the disulfide bond formation in automated protocols.
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    67. 67
      Galande, A. K.; Weissleder, R.; Tung, C. H. An effective method of on-resin disulfide bond formation in peptides. J. Comb. Chem. 2005, 7, 174– 177,  DOI: 10.1021/cc049839r
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      67
      An Effective Method of On-Resin Disulfide Bond Formation in Peptides
      Galande, Amit K.; Weissleder, Ralph; Tung, Ching-Hsuan
      Journal of Combinatorial Chemistry (2005), 7 (2), 174-177CODEN: JCCHFF; ISSN:1520-4766. (American Chemical Society)
      Five disulfide-bridged peptides were synthesized on solid phase. The peptides were assembled using std. Fmoc chem. on Wang resin with tert-butylthio (S-t-Bu) and 4-methoxytrityl (Mmt) as thiol-protecting groups for cysteines undergoing disulfide bond formation. In the first step, S-t-Bu was removed by redn. to liberate free thiol by treating the resin with 20% mercaptoethanol in DMF for 3 h. The resin was then reacted with a 10-fold excess of 2,2'-dithiobis(5-nitropyridine) (DTNB) in CH2Cl2 for 1 h, and the free thiol was thus reprotected and activated with the 5-nitropyridinesulfenyl (5-Npys) group. This was followed by the cyclization step in which the resin was treated with 1% TFA in CH2Cl2 in the the presence of triisopropylsilane (TIS) as the scavenger. The reaction was monitored by measuring the absorbance of 5-nitropyridine-2-thione at 386 nm; all cyclizations were completed in <20 min.
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    68. 68
      Postma, T. M.; Albericio, F. N-Chlorosuccinimide, an efficient reagent for on-resin disulfide formation in solid-phase peptide synthesis. Org. Lett. 2013, 15, 616– 619,  DOI: 10.1021/ol303428d
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      68
      N-Chlorosuccinimide, an Efficient Reagent for On-Resin Disulfide Formation in Solid-Phase Peptide Synthesis
      Postma, Tobias M.; Albericio, Fernando
      Organic Letters (2013), 15 (3), 616-619CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      N-Chlorosuccinimide is described as a widely applicable on-resin disulfide-forming reagent. Disulfide bond formation was completed within 15 min in DMF. This strategy was successfully used in the synthesis of oxytocin and a regioselective synthesis of an α-conotoxin. Moreover, disulfide formation with N-chlorosuccinimide was found to be compatible with oxidn.-prone methionine and tryptophan.
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    69. 69
      Altinbasak, I.; Arslan, M.; Sanyal, R.; Sanyal, A. Pyridyl disulfide-based thiol-disulfide exchange reaction: Shaping the design of redox-responsive polymeric materials. Polym. Chem. 2020, 11, 7603– 7624,  DOI: 10.1039/d0py01215g
      [Crossref], [CAS], Google Scholar
      69
      Pyridyl disulfide-based thiol-disulfide exchange reaction: shaping the design of redox-responsive polymeric materials
      Altinbasak, Ismail; Arslan, Mehmet; Sanyal, Rana; Sanyal, Amitav
      Polymer Chemistry (2020), 11 (48), 7603-7624CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      A review. Recent years have witnessed an increase in the utilization of stimuli-responsive polymers in various areas of materials and biol. sciences. In particular, disulfide linkage contg. redox-responsive polymers have attracted interest in various biomedical applications ranging from fabrication of drug delivery vehicles to diagnostic interfaces. Cleavage of the disulfide linkage in the presence of an endogenous reducing agent, namely, glutathione, also found in increased amts. in diseased tissues has led to the incorporation of this particular linkage into several therapeutic platforms. Among the various methods available for introducing the redox-sensitive disulfide unit, the pyridyl disulfide (PDS) moiety has been one of the most widely employed building blocks. The rapid thiol-disulfide exchange reaction of the PDS group with thiol functional groups has been exploited from the reversible conjugation of therapeutic agents to the fabrication of redox-responsive crosslinked materials such as hydrogels and nanogels. This review provides an overview of various synthetic approaches utilized to incorporate this particular thiol-reactive motif into different types of polymeric materials and briefly highlights its utilization to obtain functional materials.
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    70. 70
      Lee, J. Y.; Yang, S. T.; Lee, S. K.; Jung, H. H.; Shin, S. Y.; Hahm, K. S.; Kim, J. I. Salt-resistant homodimeric bactenecin, a cathelicidin-derived antimicrobial peptide. FEBS J. 2008, 275, 3911– 3920,  DOI: 10.1111/j.1742-4658.2008.06536.x
      [Crossref], [PubMed], [CAS], Google Scholar
      70
      Salt-resistant homodimeric bactenecin, a cathelicidin-derived antimicrobial peptide
      Lee, Ju Y.; Yang, Sung-Tae; Lee, Seung K.; Jung, Hyun H.; Shin, Song Y.; Hahm, Kyung-Soo; Kim, Jae I.
      FEBS Journal (2008), 275 (15), 3911-3920CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)
      The cathelicidin antimicrobial peptide bactenecin is a β-hairpin mol. with a single disulfide bond and broad antimicrobial activity. The proform of bactenecin exists as a dimer, however, and it has been proposed that bactenecin is released as a dimer in vivo, although there has been little study of the dimeric form of bactenecin. To investigate the effect of bactenecin dimerization on its biol. activity, the authors characterized the dimer's effect on phospholipid membranes, the kinetics of its bactericidal activity, and its salt sensitivity. The authors initially synthesized two bactenecin dimers (antiparallel and parallel) and two monomers (β-hairpin and linear). Under oxidative folding conditions, reduced linear bactenecin preferentially folded into a dimer forming a ladder-like structure via intermol. disulfide bonding. As compared to the monomer, the dimer had a greater ability to induce lysis of lipid bilayers and was more rapidly bactericidal. Interestingly, the dimer retained antimicrobial activity at physiol. salt concns. (150 mM NaCl), although the monomer was inactivated. This salt resistance was also seen with bactenecin dimer contg. one intermol. disulfide bond, and the bactenecin dimer appears to undergo multimeric oligomerization at high salt concns. Overall, dimeric bactenecin shows potent and rapid antimicrobial activity, and resists salt-induced inactivation under physiol. conditions through condensation and oligomerization. These characteristics shed light on the features that a peptide would need to serve as an effective therapeutic agent.
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    71. 71
      King, T. P.; Zhao, S. W.; Lam, T. Preparation of protein conjugates via intermolecular hydrazone linkage. Biochemistry 1986, 25, 5774– 5779,  DOI: 10.1021/bi00367a064
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      71
      Preparation of protein conjugates via intermolecular hydrazone linkage
      King, Te Piao; Zhao, Shu Wei; Lam, Terence
      Biochemistry (1986), 25 (19), 5774-9CODEN: BICHAW; ISSN:0006-2960.
      Proteins can be modified at their amino groups under gentle conditions to produce derivs. contg. an av. of 3-6 aryl aldehyde or acyl hydrazide groups. These 2 types of modified proteins at ∼10 μM concn. condense with each other at pH ∼5 to form conjugates linked by hydrazone bonds. Under proper conditions, conjugates contg. mainly dimers and trimers or, if desired, higher oligomers can be obtained. The conjugates can be dissocd. to their individual protein components by an exchange reaction with an excess of acetyl hydrazide. The reversible hydrazone bonds of conjugates can be reduced with NaCNBH3 to give stable hydrazide bonds. The stability of protein-hydrazone conjugates was significantly greater than that of the model compd., the N-acetylhydrazone of p-carboxybenzaldehyde. This difference is believed to result from the presence of multiple hydrazone linkages in protein conjugates.
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    72. 72
      Rádis-Baptista, G. Cell-Penetrating Peptides Derived from Animal Venoms and Toxins. Toxins 2021, 13, 147– 225,  DOI: 10.3390/toxins13020147
      [Crossref], [PubMed], [CAS], Google Scholar
      72
      Cell-penetrating peptides derived from animal venoms and toxins
      Radis-Baptista, Gandhi
      Toxins (2021), 13 (2), 147CODEN: TOXIB7; ISSN:2072-6651. (MDPI AG)
      A review. Cell-penetrating peptides (CPPs) comprise a class of short polypeptides that possess the ability to selectively interact with the cytoplasmic membrane of certain cell types, translocate across plasma membranes and accumulate in the cell cytoplasm, organelles (e.g., the nucleus and mitochondria) and other subcellular compartments. CPPs are either of natural origin or de novo designed and synthesized from segments and patches of larger proteins or designed by algorithms. With such intrinsic properties, along with membrane permeation, translocation and cellular uptake properties, CPPs can intracellularly convey diverse substances and nanomaterials, such as hydrophilic org. compds. and drugs, macromols. (nucleic acids and proteins), nanoparticles (nanocrystals and polyplexes), metals and radionuclides, which can be covalently attached via CPP N- and C-terminals or through prepn. of CPP complexes. A cumulative no. of studies on animal toxins, primarily isolated from the venom of arthropods and snakes, have revealed the cell-penetrating activities of venom peptides and toxins, which can be harnessed for application in biomedicine and pharmaceutical biotechnol. In this review, I aimed to collate examples of peptides from animal venoms and toxic secretions that possess the ability to penetrate diverse types of cells. These venom CPPs have been chem. or structurally modified to enhance cell selectivity, bioavailability and a range of target applications. Herein, examples are listed and discussed, including cysteine-stabilized and linear, a-helical peptides, with cationic and amphipathic character, from the venom of insects (e.g., melittin, anoplin, mastoparans), arachnids (latarcin, lycosin, chlorotoxin, maurocalcine/imperatoxin homologs and wasabi receptor toxin), fish (pardaxins), amphibian (bombesin) and snakes (crotamine and cathelicidins).
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    73. 73
      Huerta-Cantillo, J.; Navarro-García, F. Properties and design of antimicrobial peptides as potential tools against pathogens and malignant cells. Investig. en Discapac. 2016, 5, 96– 115
      Google Scholar
      There is no corresponding record for this reference.
    74. 74
      Dudek, M.; Romanowska, J.; Wituła, T.; Trylska, J. Interactions of amikacin with the RNA model of the ribosomal A-site: Computational, spectroscopic and calorimetric studies. Biochimie 2014, 102, 188– 202,  DOI: 10.1016/j.biochi.2014.03.009
      [Crossref], [PubMed], [CAS], Google Scholar
      74
      Interactions of amikacin with the RNA model of the ribosomal A-site: Computational, spectroscopic and calorimetric studies
      Dudek, Marta; Romanowska, Julia; Witula, Tomasz; Trylska, Joanna
      Biochimie (2014), 102 (), 188-202CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)
      Amikacin is a 2-deoxystreptamine aminoglycoside antibiotic possessing a unique L-HABA (L-(-)-γ-amino-α-hydroxybutyric acid) group and applied in the treatment of hospital-acquired infections. Amikacin influences bacterial translation by binding to the decoding region of the small ribosomal subunit that overlaps with the binding site of aminoacylated-tRNA (A-site). Here, we have characterized thermodn. of interactions of amikacin with a 27-mer RNA oligonucleotide mimicking the aminoglycoside binding site in the bacterial ribosome. We applied isothermal titrn. and differential scanning calorimetries, CD and thermal denaturation expts., as well as computer simulations. Thermal denaturation studies have shown that amikacin affects only slightly the melting temps. of the A-site mimicking RNA model suggesting a moderate stabilization of RNA by amikacin. Isothermal titrn. calorimetry gives the equil. dissocn. consts. for the binding reaction between amikacin and the A-site oligonucleotide in the micromolar range with a favorable enthalpic contribution. However, for amikacin we observe a pos. entropic contribution to binding, contrary to other aminoglycosides, paromomycin and ribostamycin. CD spectra suggest that the obsd. increase in entropy is not caused by structural changes of RNA because amikacin binding does not destabilize the helicity of the RNA model. To investigate the origins of this pos. entropy change we performed all-atom mol. dynamics simulations in explicit solvent for the 27-mer RNA oligonucleotide mimicking one A-site and the crystal structure of an RNA duplex contg. two A-sites. We obsd. that the diversity of the conformational states of the L-HABA group sampled in the simulations of the complex was larger than for the free amikacin in explicit water. Therefore, the larger flexibility of the L-HABA group in the bound form may contribute to an increase of entropy upon binding.
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    75. 75
      Pilch, D. S.; Kaul, M.; Barbieri, C. M.; Kerrigan, J. E.; Johnson, W. Thermodynamics of aminoglycoside-rRNA recognition. Biopolymers 2003, 70, 58– 79,  DOI: 10.1002/bip.10411
      [Crossref], [PubMed], [CAS], Google Scholar
      75
      Thermodynamics of aminoglycoside-rRNA recognition
      Pilch, Daniel S.; Kaul, Malvika; Barbieri, Christopher M.; Kerrigan, John E.
      Biopolymers (2003), 70 (1), 58-79CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
      2-Deoxystreptamine (2-DOS) aminoglycosides are a family of structurally related broad-spectrum antibiotics that are used widely in the treatment of infections caused by aerobic Gram-neg. bacilli. Their antibiotic activities are ascribed to their abilities to bind a highly conserved A site in the 16S rRNA of the 30S ribosomal subunit and interfere with protein synthesis. The abilities of the 2-DOS aminoglycosides to recognize a specific subdomain of a large RNA mol. make these compds. archetypical models for RNA-targeting drugs. This article presents a series of calorimetric, spectroscopic, osmotic stress, and computational studies designed to evaluate the thermodn. (ΔG, ΔH, ΔS, ΔCp) of aminoglycoside-rRNA interactions, as well as the hydration changes that accompany these interactions. In conjunction with the current structural database, the results of these studies provide important insights into the mol. forces that dictate and control the rRNA binding affinities and specificities of the aminoglycosides. Significantly, identification of these mol. driving forces which include binding-linked drug protonation reactions, polyelectrolyte contributions from counterion release, conformational changes, hydration effects, and mol. interactions (e.g., hydrogen bonds and van der Waals interactions), as well as the relative magnitudes of their contributions to the binding free energy, could not be achieved by consideration of structural data alone, highlighting the importance of acquiring both thermodn. and structural information for developing a complete understanding of the drug-RNA binding process. The results presented here begin to establish a database that can be used to predict, over a range of conditions, the relative affinity of a given aminoglycoside or aminoglycoside mimetic for a targeted RNA site vs. binding to potential competing secondary sites. This type of predictive capability is essential for establishment of a rational design approach to the development of new RNA-targeted drugs.
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    76. 76
      Kulik, M.; Goral, A. M.; Jasiński, M.; Dominiak, P. M.; Trylska, J. Electrostatic interactions in aminoglycoside-RNA complexes. Biophys. J. 2015, 108, 655– 665,  DOI: 10.1016/j.bpj.2014.12.020
      [Crossref], [PubMed], [CAS], Google Scholar
      76
      Electrostatic Interactions in Aminoglycoside-RNA Complexes
      Kulik, Marta; Goral, Anna M.; Jasinski, Maciej; Dominiak, Paulina M.; Trylska, Joanna
      Biophysical Journal (2015), 108 (3), 655-665CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      Electrostatic interactions often play key roles in the recognition of small mols. by nucleic acids. An example is aminoglycoside antibiotics, which by binding to rRNA affect bacterial protein synthesis. These antibiotics remain one of the few valid treatments against hospital-acquired infections by Gram-neg. bacteria. It is necessary to understand the amplitude of electrostatic interactions between aminoglycosides and their rRNA targets to introduce aminoglycoside modifications that would enhance their binding or to design new scaffolds. Here, we calcd. the electrostatic energy of interactions and its per-ring contributions between aminoglycosides and their primary rRNA binding site. We applied either the methodol. based on the exact potential multipole moment (EPMM) or classical mol. mechanics force field single-point partial charges with Coulomb formula. For EPMM, we first reconstructed the aspherical electron d. of 12 aminoglycoside-RNA complexes from the at. parameters deposited in the University at Buffalo Databank. The University at Buffalo Databank concept assumes transferability of electron d. between atoms in chem. equiv. vicinities and allows reconstruction of the electron densities from exptl. structural data. From the electron d., we then calcd. the electrostatic energy of interaction using EPMM. Finally, we compared the two approaches. The calcd. electrostatic interaction energies between various aminoglycosides and their binding sites correlate with exptl. obtained binding free energies. Based on the calcd. energetic contributions of water mols. mediating the interactions between the antibiotic and rRNA, we suggest possible modifications that could enhance aminoglycoside binding affinity.
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    77. 77
      Protocols for the Fmoc SPPS of Cysteine-containing Peptides. https://www.sigmaaldrich.com/PL/pl/technical-documents/protocol/chemistry-and-synthesis/peptide-synthesis/fmoc-spps-cysteine-peptides#disulfide (Accessed Jan 10, 2022).
      Google Scholar
      There is no corresponding record for this reference.
    78. 78
      Chen, L.; Annis, I.; Barany, G. Disulfide Bond Formation in Peptides. Curr. Protoc. Protein Sci. 2001, 23, 18.16.11– 18.16.19,  DOI: 10.1002/0471140864.ps1806s23
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    79. 79
      Castillo, J. I.; Równicki, M.; Wojciechowska, M.; Trylska, J. Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics on E. coli bacteria. Bioorg. Med. Chem. Lett. 2018, 28, 3094– 3098,  DOI: 10.1016/j.bmcl.2018.07.037
      [Crossref], [PubMed], [CAS], Google Scholar
      79
      Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics in E. coli
      Castillo, Jaime I.; Rownicki, Marcin; Wojciechowska, Monika; Trylska, Joanna
      Bioorganic & Medicinal Chemistry Letters (2018), 28 (18), 3094-3098CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A combination of antibacterial agents should make the emergence of resistance in bacteria less probable. Thus we have analyzed the synergistic effects between antibacterial antisense peptide nucleic acids (PNA) and conventional antibiotics against Escherichia coli AS19 (lipopolysaccharide defective) strain and a deriv. of a pathogenic strain E. coli O157:H7. PNAs were designed to target mRNA transcripts encoding the essential acyl carrier protein (gene acpP) and conjugated to the cell-penetrating peptide (KFF)3K for cellular uptake. Antibiotics included aminoglycosides, aminopenicillins, polymyxins, rifamycins, sulfonamides and trimethoprim. Synergies were evaluated using the checkerboard technique. Fractional Inhibitory Concn. indexes (FICi) were calcd. for all combinations based on the minimal inhibitory concn. of each individual agent. The results demonstrate two novel synergistic combinations of antimicrobial agents, namely, (KFF)3K-PNA anti-acpP with polymyxin B and (KFF)3K-PNA anti-acpP with trimethoprim (both with FICi = 0.38). Polymyxin B's synergy postulates cell wall targeted antibiotics as attractive agents to improve the uptake of PNA while trimethoprim's interaction with PNA my reveal a new inhibitory mechanism.
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    80. 80
      Hsieh, M. H.; Yu, C. M.; Yu, V. L.; Chow, J. W. Synergy assessed by checkerboard a critical analysis. Diagn. Microbiol. Infect. Dis. 1993, 16, 343– 349,  DOI: 10.1016/0732-8893(93)90087-n
      [Crossref], [PubMed], [CAS], Google Scholar
      80
      Synergy assessed by checkerboard. A critical analysis
      Hsieh M H; Yu C M; Yu V L; Chow J W
      Diagnostic microbiology and infectious disease (1993), 16 (4), 343-9 ISSN:0732-8893.
      The checkerboard dilution test is widely used for evaluation of in vitro synergy for multiple drugs, although problems in performance, standardization, and interpretation have been noted. A major problem inherent in this commonly used method is the use of twofold dilutions for the antibiotic concentrations. We evaluated an alternative method proposed by Horrevorts and colleagues that preserved the twofold dilution scheme. Giant checkerboards were constructed from a series of component checkerboards using rifampin and minocycline against Staphylococcus aureus. We found that this method improved the stability of the fractional inhibitory concentration (FIC) indices, but required substantially more labor and generated other problems. FIC interpretation and calculation remained compromised by the twofold dilution scheme. We have analyzed the theoretical basis of the checkerboard and its FIC calculation and conclude that the twofold dilution with its exponential increase in dilutions makes this method of synergy evaluation inherently unstable. The principle of examining growth at multiple dilutions of combined antibiotics is valid for assessment of synergy, but newer methods need to be devised.
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    • MS spectra and RP-HPLC chromatograms of AMG-derivatives, peptide, peptide-derivatives, AMG–AMP conjugates, and peptide dimers; synthesis schemes of the AMG–peptide conjugates; optical density (OD600) as a measure of E. coli K-12 MG1655, E. coli WR 3551/98, S. aureus ATCC 29213, and S. aureus BAA-1720 MRSA growth after 20 h incubation with AMG–AMP conjugates, peptide dimers, amikacin, and neomycin; and typical checkerboard test combinations determined for E. coli K12 MG1655 and S. aureus ATCC 29213 (PDF)


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