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Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains
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Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains
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  • Emma van Groesen
    Emma van Groesen
    Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
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  • Cornelis J. Slingerland
    Cornelis J. Slingerland
    Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
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  • Paolo Innocenti
    Paolo Innocenti
    Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
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  • Milos Mihajlovic
    Milos Mihajlovic
    Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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  • Rosalinde Masereeuw
    Rosalinde Masereeuw
    Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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    Orcidhttps://orcid.org/0000-0002-1560-1074
  • Nathaniel I. Martin*
    Nathaniel I. Martin
    Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0001-8246-3006
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ACS Infectious Diseases

Cite this: ACS Infect. Dis. 2021, 7, 9, 2746–2754
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https://doi.org/10.1021/acsinfecdis.1c00318
Published August 13, 2021

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Abstract

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Vancomycin functions by binding to lipid II, the penultimate bacterial cell wall building block used by both Gram-positive and Gram-negative species. However, vancomycin is generally only able to exert its antimicrobial effect against Gram-positive strains as it cannot pass the outer membrane (OM) of Gram-negative bacteria. To address this challenge, we here describe efforts to conjugate vancomycin to the OM disrupting polymyxin E nonapeptide (PMEN) to yield the hybrid “vancomyxins”. In designing these hybrid antibiotics, different spacers and conjugation sites were explored for connecting vancomycin and PMEN. The vancomyxins show improved activity against Gram-negative strains compared with the activity of vancomycin or vancomycin supplemented with PMEN separately. In addition, the vancomyxins maintain the antimicrobial effect of vancomycin against Gram-positive strains and, in some cases, show enhanced activity against vancomycin-resistant strains. The hybrid antibiotics described here have reduced nephrotoxicity when compared with clinically used polymyxin antibiotics. This study demonstrates that covalent conjugation to an OM disruptor contributes to sensitizing Gram-negative strains to vancomycin while retaining anti-Gram-positive activity.

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Vancomycin (Figure 1) is the most prominent clinically used glycopeptide antibiotic and exhibits potent activity against Gram-positive bacteria. It functions by inhibiting cell-wall biosynthesis by targeting the peptidoglycan precursor lipid II and specifically by binding the d-Ala-d-Ala terminus of the lipid II pentapeptide via a network of five hydrogen bonds. In binding to this peptidoglycan precursor, vancomycin prevents cell-wall polymerization by bacterial transpeptidases and transglycosylases which leads to decreased bacterial cell-wall integrity, eventually resulting in lysis of the bacterial cell. (1,2) Furthermore, binding of vancomycin to lipid II is enhanced by cooperative dimerization which increases the binding affinity of vancomycin to lipid II and enhances its antimicrobial activity. (3−5) While lipid II is also present in Gram-negative bacteria, vancomycin is unable to access it due to the presence of the additional outer membrane (OM) found in Gram-negatives. (6) The OM is characterized by an inner leaflet of phospholipids and an outer leaflet decorated by lipopolysaccharide (LPS). (7) Notably, the ability of vancomycin to also bind to Gram-negative lipid II from E. coli was confirmed by Shlaes and co-workers. Furthermore, this study suggested that defects in the LPS core can revert resistance of Gram-negative strains to large hydrophilic molecules such as vancomycin. (6) Additionally, in a recent investigation, Bardoel and co-workers showed that serum can sensitize multidrug resistant (MDR) K. pneumoniae to vancomycin, a process facilitated by the membrane attack complex (MAC) of the complement system found in human serum. The MAC forms pores in the OM causing disruption, allowing otherwise Gram-positive specific antimicrobials to also exert their action against Gram-negative strains. (8) These studies, and others carried out in the same area, highlight the potential of vancomycin to be effective against Gram-negative bacteria when the integrity of the OM is compromised.

Figure 1

Figure 1. Structures of clinically used antibiotics vancomycin and colistin (polymyxin E), with the colistin-derived polymyxin E nonapeptide (PMEN) also indicated.

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Different strategies to sensitize Gram-negative bacteria to antibiotics which typically only work against Gram-positive pathogens have been explored in the literature. (9−11) The two main approaches used most often rely on (a) covalent attachment of OM-disrupting or OM-bypassing moieties and (b) coadministration with “adjuvants”, which can either affect the OM integrity or impair the bacteria’s efflux system. (7,12,13) Previously described covalent conjugates include those reported by Miller and co-workers wherein vancomycin was linked to an iron sequestering siderophore mimetic to yield hybrids with slightly reduced activity against Gram-positive strains but with enhanced activity toward a hypersensitive strain of Pseudomonas aeruginosa under iron depleted conditions. (14) More recently, the group of Haldar reported a lipophilic cationic vancomycin analogue, VanQAmC10, which was shown to be bactericidal against MDR A. baumannii. (15) Another recent vancomycin derivative, developed by the groups of Wender and Cegelski, involves the introduction of an arginine-amide moiety at the vancomycin C-terminus, significantly enhancing activity against E. coli (MIC 8–16 μM) including resistant strains. (16,17) Notably, this arginine-vancomycin conjugate was demonstrated to successfully reduce bacterial burden >6-log fold compared to vehicle and vancomycin in a murine thigh E. coli infection model. (16) In addition to such covalent approaches to enhance anti-Gram-negative activity, agents capable of potentiating or synergizing with Gram-positive-specific antibiotics also present an attractive option. In this regard, many OM-disrupting cyclic or linear cationic peptides have been reported to sensitize Gram-negative pathogens to anti-Gram-positive antibiotics including vancomycin. (10,18,19)
Among the most notable OM disrupting agents are the so-called polymyxin nonapeptides which are derived from the clinically used antibiotics polymyxin B and polymyxin E (colistin). Readily obtained by enzymatic degradation of the full-length antibiotic, the cyclic nonapeptides lack the fatty acyl tail and N-terminal Dab residue present in the parent polymyxins (Figure 1). Due to its associated (nephro)toxicity when administered systemically, colistin has traditionally only been used as an antibiotic of last resort. (20) However, given increasing rates of resistance, the use of colistin is now on the rise. (20) By comparison, the polymyxin nonapeptides are significantly less toxic than the parent compounds (21,22) but still maintain the capacity to bind to Gram-negative bacteria by recognition of the Lipid A unit of LPS. (23,24) Given their high positive charge, polymyxin nonapeptides displace the divalent cations responsible for stabilizing membrane packing in the Gram-negative OM (25) resulting in disruption of the OM. (20) Notably, while polymyxin nonapeptides retain little-to-none of the activity of the parent antibiotic, (26) they function effectively as synergistic agents and can improve the activity of otherwise Gram-positive specific antibiotics including vancomycin. (18,19)
To date, a small number of studies have explored the effect of conjugating polymyxins to antibiotic agents with the aim of using the covalently attached OM disruptor as an adjuvant for the antimicrobial agent. Generally speaking, these studies have focused on conjugation with Gram-negative active antibiotics. In a recent example, Schweizer and co-workers described the ligation of full-length polymyxin B to the aminoglycoside tobramycin. (27) The resulting hybrid did not outperform either polymyxin or tobramycin in direct activity but interestingly did potentiate other antibiotics toward several P. aeruginosa strains, including MDR isolates. (27) In another even newer development, researchers at Polyphor described bicyclic hybrids comprising a monocyclic β-hairpin peptidomimetic of protegrin I and PMEN. (28) While neither monocyclic peptide exhibits significant activity on its own, the bicyclic hybrids demonstrated extremely potent activity both in vitro and in mouse models of infection with a range of Gram-negative pathogens. Notably, these bicyclic constructs are proposed to target the extracellular part of the OM protein BamA, thereby avoiding the need to pass the OM. (28)
Given previous reports showing that covalent attachment of siderophores, LPS binding moieties, or positively charged moieties to vancomycin can lead to improved antimicrobial activity against Gram-negative strains, (15−17,29,30) we hypothesized that conjugation of vancomycin to the highly positively charged OM disruptor PMEN could sensitize Gram-negative strains. Our interest in exploring vancomycin-PMEN conjugates was further spurred given that OM disruption has also previously been demonstrated to enable anti-Gram-negative activity for vancomycin. (6,8,10,18,19) Also of note are recent reports showing that the covalent attachment of cationic moieties to vancomycin is an effective means to resensitize clinically relevant vancomycin-resistant Gram-positive strains. (15,31−35) For these reasons, we anticipated that vancomycin-PMEN conjugates might exhibit enhanced activity toward drug-resistant Gram-positive strains as well. Here, we report the synthesis and evaluation of the vancomyxins: a new class of vancomycin-PMEN hybrid antibiotics. The antimicrobial activities of the vancomyxins against Gram-positive and Gram-negative bacteria (including drug-resistant clinical isolates) as well as an assessment of their toxicity toward eukaryotic cells is here reported.

Results and Discussion

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As a strategy for preparing the vancomycin/PMEN conjugates we envisioned the use of so-called “click chemistry”, wherein complementary azide and alkyne containing precursors are covalently linked by means of the well-established copper-catalyzed azide–alkyne cycloaddition reaction. (36−38) In pursuing this approach, we opted to add the required azide handle to the N-terminus of the PMEN moiety while the alkyne functionality was incorporated into the vancomycin structure at two different locations (Scheme 1).

Scheme 1

Scheme 1. Vancomyxins Prepared in Present Studya
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aReagents and conditions used: (i) CuSO4 pentahydrate, sodium ascorbate, H2O.

The azido-modified PMEN building blocks were obtained via a convenient semisynthetic approach starting from colistin. In short, degradation of colistin using the readily available enzyme ficin yielded PMEN which was subsequently converted to PMEN-Boc4 wherein the four Dab side chains are selectively protected and the N-terminus remains free. (39) Subsequently, azido-carboxylic acids of varying lengths were coupled to the N-terminus of PMEN-Boc4 using BOP/DIPEA. Following Boc-deprotection and HPLC purification, the azide-modified PMEN building blocks 3–5 where obtained (Scheme 1). In the case of the alkyne-modified vancomycin partners, we followed a previously described protocol reported by Sharpless and co-workers who used click chemistry approaches in preparing various dimers of vancomycin. (38) To this end, an alkyne handle was incorporated at either the vancomycin C-terminus or at the vancosamine moiety. Given that neither of these modifications impacts the lipid II binding core of vancomycin, it was expected that structural alterations at these sites would not impair the ability of vancomycin to recognize its target. To install the alkyne at the C-terminus, vancomycin was treated with propargyl amine and HBTU/DIPEA resulting in building block 6. For the preparation of building block 7, installation of the alkyne handle at the vancosamine moiety was achieved via reductive amination using a known alkyne-containing aromatic aldehyde (see Scheme 1 and Supporting Information Schemes S1–S2). (31,38) With the required PMEN-azides and vancomycin-alkynes in hand, the conjugation step involving triazole formation was achieved by means of copper catalysis. (36−38) In all cases, the ligation reactions proceeded cleanly and rapidly to yield the expected vancomyxins (8–13). As indicated in Scheme 1, compounds 8 and 11 feature the shortest spacer deriving from the azido glycine modified PMEN, compounds 9 and 12 contain a 5-carbon moiety, while compounds 10 and 13 include a longer and more hydrophilic PEG3 spacer.
PMEN azides 3-5, the alkyne modified vancomycins 6 and 7, and the resulting hybrid vancomyxins 8-13 were all assessed for antibacterial activity. As expected, compounds 3-5 were significantly less active than colistin (see Supporting Information Table S1) while compounds 6 and 7 showed activity comparable to vancomycin (see Supporting Information Table S2). The vancomyxins 8-13 were initially assessed against two Gram-negative and two Gram-positive strains (Table 1). Notably, against the Gram-negative E. coli ATCC25922 strain used, the vancomyxins displayed improved antimicrobial activity, with a >8-fold reduction in MIC compared to vancomycin observed for compounds 8, 9, 11, 12 (MIC going from >128 to 16 μg/mL). The decrease in MIC values was less pronounced for the compounds with PEG3-based spacers 10 and 13. Against the K. pneumoniae ATCC27736 strain used, vancomyxin 11 was found to have an MIC of 8 μg/mL, a > 16-fold improvement with respect to vancomycin, while the other vancomyxins were also found to have increased potencies in the range of >4- to >8-fold (Table 1). In the case of the Gram-positive B. subtilis and S. aureus ATCC29213 strains used in this preliminary screen, it was found that conjugation of PMEN to vancomycin did not significantly impair anti-Gram-positive activity relative to the parent vancomycin.
Table 1. Preliminary Antibacterial Activity Assessment of Vancomyxins 8-13
 MIC (μg/mL)a
Strain IDVancomycin8910111213
Gram-negative bacteria
E. coli ATCC25922>128161632161632
K. pneumoniae ATCC27736>12832166481632
Gram-positive bacteria
B. subtilis 1680.250.50.250.50.250.251
S. aureus ATCC292130.1250.250.250.250.250.250.5
a

MIC = Minimum inhibitory concentration.

In assessing these preliminary results, it was notable that compounds 10 and 13 consistently exhibited higher MIC values compared to the other vancomyxins, indicating that shorter spacers are preferable. In addition, the location used for attachment of the PMEN moiety to vancomycin (C-terminus or vancosamine) was found to have minimal impact on antibacterial activity, with MIC values differing by no more than 2-fold for the same spacers. Compound 11, wherein the PMEN motif is connected to the vancosamine functionality, performed particularly well. On the basis of these results against Gram-negative and Gram-positive strains, conjugates 8, 9, 11, and 12 were selected for further assessment and vancomyxin 11 for further modification.
As noted above, recent studies by the groups of Wender and Cegelski have shown that C-terminal modification of vancomycin with a positively charged amino acid (arginine-amide) leads to a significant improvement of anti-Gram-negative activity. These reports prompted us to synthesize two additional compounds building upon vancomyxin 11 wherein either a glycine amide or arginine amide was coupled to the C-terminus of 11. In doing so, it is possible to probe the influence of charge at the C-terminus: while the parent vancomyxin 11 contains a negative charge, analogues 14 and 15 are neutral and positively charged, respectively (Figure 2). Vancomyxins 14 and 15 were prepared by coupling either glycine amide or arginine amide to the C-terminus of vancomycin alkyne building block 7 (see Supporting Information Scheme S2). Subsequent copper-catalyzed click ligation to azido-PMEN building block 3 yielded analogues 14 and 15. An expanded antibacterial activity assessment using a variety of Gram-negative and Gram-positive strains was then performed for vancomyxins 14 and 15 along with compounds 8, 9, 11, and 12, which were identified as most promising in the initial screen (Table 2).

Figure 2

Figure 2. Structures of the vancomyxins 11, 14, and 15 with ionization state at neutral pH.

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Table 2. Expanded Assessment of 8, 9, 11, 12, 14, and 15 against Gram-Negative and Gram-Positive Bacteriaa
 MIC (μg/mL)
 Strain IDVancomycinPMENVancomycin +8 μg/mL PMEN8911121415
Gram-negative bacteria
E. coliATCC25922>128>12832161616161616
ATCC35218128>128321616161688
K. pneumoniaeATCC13883>128>1281283232881632
ATCC27736>128>12812832168161616
A. baumanniiATCC17978>128>128128128643232128128
BAA-747>128>128128326432321632
P. aeruginosaATCC10145>128>12816>128>12864643232
ATCC27853>128>1284163216161616
Gram-positive bacteria
B. subtilis1680.25>128ND0.50.250.250.25≤0.008≤0.008
S. simulans220.125>128ND≤0.0080.0310.0310.016≤0.008≤0.008
S. aureusMSSA ATCC292130.125>128ND0.250.250.250.250.251
MRSA USA3000.25>128ND0.50.250.250.250.251
VISA LIM-24>1284222428
VISA NRS4028>12881688284
VRSA 2 (vanA)128>128128326464128>128>128
VRSA 3b (vanA)>128>128>12832>12832>128>128>128
E. faecalisVRE E1246 (vanA)>128>128>128>128>128>128>128>128>128
VRE E7406(vanB)32>1283286464128128128
E. faeciumVSE E9800.5>128ND0.250.250.250.250.1250.125
VRE E155 (vanA)>128>128>12864646464648
VRE E7314 (vanB)128>12812828280.50.031
a

MIC = Minimum inhibitory concentration, ND = not determined, PMEN = Polymyxin E nonapeptide, MSSA = Methicillin-sensitive S. aureus, MRSA = Methicillin-resistant S. aureus, VISA = Vancomycin-intermediate S. aureus, VRSA = Vancomycin-resistant S. aureus, VSE = Vancomycin-sensitive Enterococci, VRE = Vancomycin-resistant Enterococci.

Activity against Gram-Negative Bacteria

As anticipated, neither vancomycin nor PMEN showed any activity against the Gram-negative strains tested when administered on their own. However, the addition of 8 μg/mL PMEN to vancomycin resulted in increased activity against E. coli (≥4-fold), K. pneumoniae and A. baumannii (both ≥2-fold), as well as P. aeruginosa (≥8/16-fold). This synergistic effect of PMEN with vancomycin is in accordance with previous studies. (18,19) In the case of vancomyxins, 8, 9, 11, 12, 14, and 15, however, the covalent linking of the vancomycin and PMEN units was found to enhance the activity against most of the strains tested. Against the two E. coli strains used, all six vancomyxins showed improved activity relative to the vancomycin/PMEN combination. Notably, the C-terminally modified 14 and 15 exhibited the greatest enhancement with a 4-fold improvement in activity against E. coli ATCC35218, reaching MICs as low as 8 μg/mL. When tested against K. pneumoniae, the vancomyxins typically displayed a 4- to 8-fold improved activity compared with the vancomycin/PMEN combination, which itself showed little effect. In this case, 11 was found to be the most active compound with an MIC of 8 μg/mL against both Klebsiella strains tested and 12 with an MIC of 8 μg/mL against K. pneumoniae ATCC13883 (a 16-fold enhancement relative vancomycin + 8 μg/mL PMEN). Similarly, in assays with A. baumannii, the vancomycin/PMEN combination was only moderately active (MIC 128 μg/mL) while the vancomyxins showed 2- to 8-fold improvements in antibacterial activity. Interestingly, while the covalently linked vancomyxins show enhanced activity compared to vancomycin supplemented with PMEN against E. coli, K. pneumoniae, and A. baumannii, the opposite pattern was observed in the case of P. aeruginosa. Against P. aeruginosa ATCC10145 vancomycin supplemented with 8 μg/mL PMEN exhibited an MIC of 16 μg/mL (an >8-fold enhancement) while the vancomyxyins showed little to no improvement relative to vancomycin. A similar trend was observed with P. aeruginosa ATCC27853. While the vancomyxins in this case generally displayed an >8-fold reduction in MIC compared to vancomycin alone (16 μg/mL vs >128 μg/mL), PMEN supplementation strongly synergized with vancomycin reducing its MIC to 4 μg/mL. The greater sensitivity of the P. aeruginosa strains to the vancomycin/PMEN combination versus the larger covalently linked vancomyxins may be attributable to the known low-permeability of the P. aeruginosa outer membrane. (40) Furthermore, previous investigations have established that Pseudomonas strains are particularly sensitive to the polymyxin antibiotics as well as the synergistic effects of the corresponding nonapeptides when coadministered with other Gram-positive specific antibiotics. (41,42)

Activity against Gram-Positive Bacteria

In assessing the activity of the vancomyxins against Gram-positive bacteria, a number of vancomycin-sensitive (MIC ≤ 2 μg/mL), vancomycin-intermediate (MIC 4–8 μg/mL), and vancomycin-resistant (≥16 μg/mL) strains were selected (Table 2). For the vancomycin-intermediate and vancomycin-resistant strains, the effect of PMEN addition at 8 μg/mL was also investigated which, not surprisingly, had no impact on the reduced potency of vancomycin. This lack of synergy was expected given that PMEN serves as an OM disruptor, a barrier only present in Gram-negative strains. Among the vancomycin-sensitive strains tested (MSSA, MRSA, and VSE) the vancomyxins were found to exhibit a similar or slightly enhanced activity relative to vancomycin. Notably, when assessed against B. subtilis, compounds 8, 9, 11, and 12 were found to be as active as vancomycin, while 14 and 15 were found to be extremely potent with activities below 0.008 μg/mL, a >32-fold improvement. Similarly, all the vancomyxins showed significantly increased potency compared to vancomycin against the strain of S. simulans tested. When tested against VISA, the vancomyxins demonstrated potencies similar or slightly enhanced relative to vancomycin. Interestingly, however, against VRSA, compounds 9, 12, 14, and 15 were found to show no enhancement of activity while compounds 8 and 11 displayed improved antibacterial potencies with a ≥4-fold reduction of MIC values compared to vancomycin. Among the VRE strains tested, the activities of the vancomyxins relative to vancomycin were found to be highly variable. Against vancomycin-resistant E. faecalis, the vancomyxins showed little-to-no enhancement whereas against vancomycin-resistant E. faecium, particularly the VanB type, the vancomyxins exhibited potent antibacterial activity. Specifically, for the VanB type E. faecium strain tested, vancomyxins 9 and 12 have an MIC of 8 μg/mL and vancomyxins 8 and 11 have MIC values of 2 μg/mL, while 14 and 15 demonstrated even more impressive potencies with MICs of 0.5 and 0.031 μg/mL, respectively.
The enhanced antimicrobial activities observed for the vancomyxins against vancomycin-resistant strains suggest that our novel compounds are able to (partially) compensate for the reduced binding of the vancomycin core to the d-Ala-d-Lac lipid II motif, common to VREs containing either vanA or vanB resistance genes. It is well established that mutation of the d-Ala-d-Ala unit found in wild type lipid II to the d-Ala-d-Lac unit found in VanA or VanB positive strains results in a >1000-fold reduction in binding affinity for vancomycin and loss of antimicrobial activity. (1,2,4,43) The finding that the vancomyxins overcome this resistance, especially in the case of VanB positive E. faecium, indicates that other structural features are contributing to their enhanced activity. Specifically, the large positive net charge introduced by conjugating the PMEN motif to vancomycin may facilitate electrostatic interactions with the negatively charged bacterial membrane. This in turn may lead to increased membrane anchoring and lipid II engagement thereby interfering with cell wall synthesis and lowering the MIC of the vancomyxins toward otherwise vancomycin-resistant strains. In this regard, it is noteworthy that previous reports have also described the addition of positively charged moieties to vancomycin as means of overcoming vancomycin resistance. (4,15,31−35) Furthermore, conjugation of vancomycin to bacteriocin nisin (1–12) has previously shown to reduce the MIC against VRE. (44)
As described above, vancomyxins 14 and 15 were synthesized to assess if a difference in charge at the C-terminus (neutral and positive) compared to 11 (negative) would enhance activity. Against Gram-negative strains, this did not appear to have a large effect on activity as the MICs of vancomyxins 11, 14, and 15 are generally similar, differing by no more than 2-fold. Against Gram-positive strains, however, there are notable species-dependent differences; against VRSA, the negatively charged C-terminus of 11 results in activity superior to that of the neutral 14 and positive-charged 15, while against vancomycin-resistant E. faecium, the positively charged 15 exhibits enhanced activity.
From a mechanistic perspective, we hypothesized that the enhanced anti-Gram-negative activity of the vancomyxins compared to vancomycin might be due to the ability of PMEN to bind LPS and disrupt the outer membrane. (23,24) To investigate this, we performed an LPS antagonization assay which indeed points to an interaction of compound 11 with LPS, as its MIC against E. coli ATCC25922 increased significantly from 16 μg/mL to >128 μg/mL when incubated with exogenous LPS (see Supporting Information Table S4).

Cell-based toxicity studies

In parallel to the antibacterial activity assays, the hemolytic properties of the vancomyxins were also assessed, revealing them to be nonhemolytic up to the highest concentration tested (512 μg/mL). These findings are in line with our expectations given the nonhemolytic nature of both vancomycin and colistin (see Supporting Information Figure S1). We next turned our attention to evaluating the nephrotoxicity of the vancomyxins. Reports in the literature indicate that both polymyxins and vancomycin can impair kidney function. (45,46) In particular, proximal tubule epithelial cells are known to be sensitive to the polymyxins as a result of extensive reabsorption and intracellular accumulation. (46) In addition, proximal tubule cells have been previously used to characterize the cytotoxic effects of vancomycin. (47) To compare the hybrid vancomyxins with the corresponding parent compounds, their nephrotoxicity was assessed by means of a viability assay using conditionally immortalized proximal tubule epithelial cells (ciPTECs), with relative mitochondrial activity after 24 h as the end point measurement. In these assays, polymyxin B was found to exhibit relatively high nephrotoxicity (TC50 = 0.07 mM) while vancomycin and PMEN were significantly less toxic (>50% viability at a concentration of 1 mM for both). By comparison, the vancomyxins were found to exhibit intermediate toxicity toward ciPTECs with TC50 values ranging from 0.11 mM for compound 15 to 0.37 mM for compound 8 (see Supporting Information Figure S2 for full details), concentrations generally multiple orders of magnitude higher than the corresponding MIC values.

Conclusion

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While vancomycin is an important antibiotic for the treatment of hospitalized patients with Gram-positive infections, it has little activity against Gram-negative bacteria due to the inaccessibility of its target. Given that vancomycin can bind to the Gram-negative form of lipid II, (6) OM disruptors present a possible means for enhancing the activity of vancomycin against Gram-negative pathogens. (8,10,18,19) To this end, combination strategies involving polymyxin nonapeptide or other OM disruptors have been explored. (10,18,19) However, the covalent conjugation of vancomycin to the OM disrupting PMEN motif has not been previously described. In this study, we report a new class of vancomycin-PMEN hybrids, the vancomyxins. The vancomyxins maintain the activity of vancomycin against vancomycin-sensitive strains and, in some cases, also overcome vancomycin-resistance in Gram-positive organisms. Against Gram-negative organisms, the vancomyxins also show enhanced activity that was generally superior to that observed with a simple combination of vancomycin with PMEN. It is worth noting that when comparing the activities of the hybrid vancomyxins to vancomycin or the combination of vancomycin/PMEN, the conventional concentration units of μg/mL was used. However, given that the molecular weights of the vancomyxins are approximately double that of vancomycin, the differences in MIC are even more pronounced when comparing the appropriate molar concentrations (see Supporting Information Tables S1–S3). In addition, LPS binding of the vancomyxins is confirmed. Furthermore, the vancomyxins are not hemolytic and exhibit lower toxicity against kidney cells compared to the clinically used polymyxin B. In summary, these findings indicate that the covalent attachment of an OM disrupting PMEN motif to vancomycin is a viable strategy for enhancing anti-Gram-negative activity.

Methods

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Synthetic Procedures

The synthesis of all intermediates and of the vancomyxins is described in detail in the Supporting Information. Given here is the general procedure for the copper-catalyzed azide–alkyne cycloaddition used to prepare the vancomyxins: The ligation protocol used generally followed that previously described by Silverman et al. (38) In short, to a solution of the vancomycin alkyne (0.03 mmol, 1 equiv) in water (1.5 mL), the PMEN azide (0.03 mmol, 1 equiv) in water (1.5 mL) was added. Subsequently, sodium ascorbate (0.008 mmol, 0.25 equiv) and CuSO4·5H2O (0.003 mmol, 0.1 equiv) were added and the mixture was allowed to stir at RT for 16 h. The reaction mixture was directly purified using preparative high performance liquid chromatography (HPLC) using a C18 column (25 × 250 mm, 10 μm) with UV detection at 214 nm. The following method was used: flow rate = 12 mL/min; solvent A, 0.1% TFA in H2O/acetonitrile 95:5, and solvent B, 0.1% TFA in H2O/acetonitrile 5:95. The gradient elution was as follows: 95:5 (A/B) for 5 min, 95:5 to 40:60 (A/B) over 50 min, 40:60 to 0:100 (A/B) for 1 min, 0:100 (A/B) for 2 min, then reversion back to 95:5 (A/B) over 1 min, 95:5 (A/B) for 2 min. Fractions were immediately freeze-dried and subsequently analyzed by LCMS. Pure product containing fractions were redissolved, pooled, and lyophilized to yield the vancomyxins as white powders.

Broth Microdilution Assays

From glycerol stocks, bacteria were plated out on blood agar plates overnight at 37 °C. One colony was transferred to growth media and grown at 37 °C at 200 rpm to exponential growth phase as determined by OD600. The growth media used for most strains was cation adjusted Mueller Hinton Broth (0.5 mM Mg2+ and Ca2+) + 0.002% of polysorbate 80 (p80), except for all Enterococci and VISA/VRSA strains, for which the positive control was unable to grow well in this media; therefore, TSB + 0.002% p80 was used in these cases. For VRSA, the media was supplemented with 6 μg/mL vancomycin at this stage. At OD600 = 0.5, the bacteria were diluted 100-fold and 50 μL was added to a 2-fold serial dilution series of test compound (50 μL) to reach a total volume of 100 μL per well. The 96-well polypropylene plates were incubated at 37 °C at 600 rpm overnight (18–20 h for Gram-negative strains, 20–24 h for Gram-positive strains), and plates were inspected for visual bacterial growth. Synergy experiments were performed in a similar manner as the MIC assay, except 8 μg/mL PMEN final concentration was added to the wells. LPS antagonization assays were performed in a similar manner except that a final concentration of 1 mg/mL LPS was added to the wells. In this case, colistin was used as a control. MICs are reported as the median of triplicates.

Hemolysis Assays

Defibrinated whole sheep blood was centrifuged for 15 min at 4 °C (400 g). The top layer was discarded, and the bottom layer was washed with phosphate buffered saline (PBS) and centrifuged for 15 min at 4 °C (400 g). Washing cycles were repeated at least three times. In polypropylene 96-well microtiter plates, 10-fold serial dilutions of antibiotics in PBS with 0.002% p80 in biological triplicates were added (75 μL) and an equal volume of packed blood cells diluted 25x in PBS with 0.002% p80 (75 μL) was added to all wells. Plates were incubated for 20 h at 37 °C with continuous shaking (500 rpm). After incubation, plates were centrifuged for 5 min (800 g) and 25 μL of supernatant was transferred to a clear UV-star flat-bottom polystyrene 96-well plate already containing 100 μL H2O per well. Absorption was measured at 415 nm. Data were corrected by subtraction of the background response of 1% DMSO in the presence of cells with no antibiotic and normalized using the absorbance of 0.1% Triton X-100 with blood cells as 100% hemolysis control.

PTECs Assay

Cell culture

ciPTECs overexpressing organic anion transporter 1 (OAT-1) (48,49) were cultured in DMEM/F12 medium, supplemented with fetal calf serum (10%), insulin (5 μg/mL), transferrin (5 μg/mL), selenium (5 μg/mL), hydrocortisone (35 ng/mL), Epidermal Growth Factor (10 ng/mL), and tri-iodothyronine (40 pg/mL). Cells were cultured at 33 °C for sustained proliferation. For the experiment, cells were washed with HBSS and detached by incubating them with Accutase solution for 5 min at 37 °C. Density was adjusted to 2.0 × 105 cells/mL of which 100 μL was added to each well of a 96-well plate. Seeded cells were incubated for 24 h at 33 °C, followed by 6 days incubation at 37 °C to allow them to fully differentiate. Medium was refreshed every second or third day. All cells were grown in a humidified atmosphere containing 5% (v/v) CO2.

Cell Viability Assay

Cytotoxicity was assessed using PrestoBlue cell viability reagent. Compounds were dissolved and diluted in serum free medium. Differentiated ciPTECs were washed once with HBSS and exposed to the compounds for 24 h at 37 °C. Afterward, cells were washed with HBSS and incubated with 10% PrestoBlue reagent in HBSS at 37 °C for 1 h in the dark. Fluorescence was recorded using excitation wavelength of 530 nm and emission wavelength of 590 nm. Raw data were corrected for PrestoBlue background fluorescence and reported relative to the no-treatment control (cells with medium only). Data were fitted with Graphpad Prism software by nonlinear regression with 0 as constraint to obtain TC50 values. Presented data are based on triplicates and presented as mean ± SEM.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00318.

  • Synthetic schemes and synthesis of all building blocks; analytical RP-HPLC traces, HRMS analysis and yields for all new compounds synthesized; additional MIC analysis of building blocks and control compounds; MIC analysis in μM; hemolytic and PTEC toxicity data (PDF)

Terms & Conditions

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 Author
  • Authors
    • Emma van Groesen - Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
    • Cornelis J. Slingerland - Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
    • Paolo Innocenti - Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
    • Milos Mihajlovic - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
    • Rosalinde Masereeuw - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands;  Orcidhttps://orcid.org/0000-0002-1560-1074
  • Author Contributions

    These authors contributed equally to this work.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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Financial support provided by the European Research Council (ERC consolidator grant to NIM, grant agreement no. 725523).

References

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This article references 49 other publications.

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    The global emergence of multidrug-resistant Gram-neg. bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clin. relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Addnl., efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technol. advances have allowed for an in-depth understanding of the structural and biochem. basis, substrate profiles, mol. regulation, and inhibition of MDR pumps. However, the development of clin. useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clin. significance, together with methodol. considerations for the characterization of MDR pumps.
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  13. 13
    Zabawa, T. P., Pucci, M. J., Parr, T. R., and Lister, T. (2016) Treatment of Gram-Negative Bacterial Infections by Potentiation of Antibiotics. Curr. Opin. Microbiol. 33, 7– 12,  DOI: 10.1016/j.mib.2016.05.005
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    13
    Treatment of Gram-negative bacterial infections by potentiation of antibiotics
    Zabawa, Thomas P.; Pucci, Michael J.; Parr, Thomas R.; Lister, Troy
    Current Opinion in Microbiology (2016), 33 (), 7-12CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)
    Infections caused by antibiotic-resistant pathogens, particularly Gram-neg. bacteria, represent significant treatment challenges for physicians resulting in high rates of morbidity and mortality. The outer membrane of Gram-neg. bacteria acts as a permeability barrier to many compds. that would otherwise be effective antibacterial agents, including those effective against Gram-pos. pathogens. Potentiator mols. disrupt this barrier allowing entry of otherwise impermeant mols., thus providing a strategy to render multi-drug resistant pathogens susceptible to a broader range of antibiotics. Potentiator mols. are cationic and the mechanism of disruption involves interaction with the neg. charged outer membrane. This phys. attribute, along with an often high degree of lipophilicity typically endears these mols. with unacceptable toxicity. Presented herein are examples of advanced potentiator mols. being evaluated for use in combination therapy for the treatment of resistant Gram-neg. infections.
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  14. 14
    Ghosh, M. and Miller, M. J. (1996) Synthesis and in Vitro Antibacterial Activity of Spermidine-Based Mixed Catechol- and Hydroxamate-Containing Siderophore--Vancomycin Conjugates. Bioorg. Med. Chem. 4 (1), 43– 48,  DOI: 10.1016/0968-0896(95)00161-1
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    14
    Synthesis and in vitro antibacterial activity of spermidine-based mixed catechol- and hydroxamate-containing siderophore-vancomycin conjugates
    Ghosh, Manuka; Miller, Marvin J.
    Bioorganic & Medicinal Chemistry (1996), 4 (1), 43-8CODEN: BMECEP; ISSN:0968-0896. (Elsevier)
    The first antibiotic conjugates of vancomycin with siderophore analogs contg. spermidine-based catechol ligands or mixed catechol and hydroxamate ligands are described. The design of the conjugates was based on the earlier observation that conjugation of siderophore components to β-lactam antibiotics induced active iron transport-mediated drug delivery. The novel conjugates were synthesized by selective acylation of the primary amino group of vancomycin. Preliminary biol. studies indicted that siderophore modified vancomycins lost some activity (4- to 16-fold) against Gram-pos. bacteria relative to vancomycin itself, and were generally similar to vancomycin in activity against Gram-neg. bacteria under iron-sufficient conditions. However, under iron-depleted conditions which mimic human serum, the conjugate contg. the spermidine-based catechol ligand displayed enhanced antibacterial activity against an antibiotic hypersensitive strain of Pseudomonas aeruginosa.
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  15. 15
    Sarkar, P., Samaddar, S., Ammanathan, V., Yarlagadda, V., Ghosh, C., Shukla, M., Kaul, G., Manjithaya, R., Chopra, S., and Haldar, J. (2020) Vancomycin Derivative Inactivates Carbapenem-Resistant Acinetobacter Baumannii and Induces Autophagy. ACS Chem. Biol. 15 (4), 884– 889,  DOI: 10.1021/acschembio.0c00091
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    15
    Vancomycin Derivative Inactivates Carbapenem-Resistant Acinetobacter baumannii and Induces Autophagy
    Sarkar, Paramita; Samaddar, Sandip; Ammanathan, Veena; Yarlagadda, Venkateswarlu; Ghosh, Chandradhish; Shukla, Manjulika; Kaul, Grace; Manjithaya, Ravi; Chopra, Sidharth; Haldar, Jayanta
    ACS Chemical Biology (2020), 15 (4), 884-889CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    Vancomycin is a std. drug for the treatment of multidrug-resistant Gram-pos. bacterial infections. Albeit, development of resistance (VRE, VRSA) and its inefficacy against persistent infections is a demerit. It is also intrinsically inactive against Gram-neg. bacteria. Herein, we report a vancomycin deriv., VanQAmC10, that addresses these challenges. VanQAmC10 was rapidly bactericidal against carbapenem-resistant A. baumannii (6 log10 CFU/mL redn. in 6 h), disrupted A. baumannii biofilms, and eradicated their stationary phase cells. In MRSA infected macrophages, the compd. reduced the bacterial burden by 1.3 log10 CFU/mL while vancomycin exhibited a static effect. Further investigation indicated that the compd., unlike vancomycin, promoted the intracellular degradative mechanism, autophagy, in mammalian cells, which may have contributed to its intracellular activity. The findings of the work provide new perspectives on the field of glycopeptide antibiotics.
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  16. 16
    Neville, L. F., Shalit, I., Warn, P. A., Scheetz, M. H., Sun, J., Chosy, M. B., Wender, P. A., Cegelski, L., and Rendell, J. T. (2021) In Vivo Targeting of Escherichia Coli with Vancomycin-Arginine. Antimicrob. Agents Chemother. 65 (4), e02416– 20,  DOI: 10.1128/AAC.02416-20
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    16
    In vivo targeting of Escherichia coli with vancomycin-arginine
    Neville, Lewis f.; Shalit, Itamar; Warn, Peter a.; Scheetz, Marc h.; Sun, Jiuzhi; Chosy, Madeline b.; Wender, Paul a.; Cegelski, Lynette; Rendell, Jacob t.
    Antimicrobial Agents and Chemotherapy (2021), 65 (4), e02416CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to Gram-neg. bacteria was investigated. Its MIC towards Escherichia coli, including β-lactamase expressing Ambler classes A, B, and D, was 8 to 16 μg/mL. Addn. of 8 times the MIC of V-r to E. coli was acutely bactericidal and assocd. with a low frequency of resistance (<2.32 x 10-10). In vivo, V-r markedly reduced E. coli burden by >7 log10 CFU/g in a thigh muscle model. These data warrant further development of V-r in combating E. coli, including resistant forms.
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  17. 17
    Antonoplis, A., Zang, X., Wegner, T., Wender, P. A., and Cegelski, L. (2019) Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant E. Coli and Targets Cell-Wall Synthesis. ACS Chem. Biol. 14 (9), 2065– 2070,  DOI: 10.1021/acschembio.9b00565
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    17
    Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant E. coli and Targets Cell-Wall Synthesis
    Antonoplis, Alexandra; Zang, Xiaoyu; Wegner, Tristan; Wender, Paul A.; Cegelski, Lynette
    ACS Chemical Biology (2019), 14 (9), 2065-2070CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    The emergence of multi-drug-resistant Gram-neg. bacteria, including carbapenem-resistant Enterobacteriaceae, is a major health problem that necessitates the development of new antibiotics. Vancomycin inhibits cell-wall synthesis in Gram-pos. bacteria but is generally ineffective against Gram-neg. bacteria and is unable to penetrate the outer membrane barrier. To det. whether vancomycin and other antibiotics effective against Gram-pos. bacteria could, through modification, be rendered effective against Gram-neg. bacteria, we discovered that the covalent attachment of a single arginine to vancomycin yielded conjugates with order-of-magnitude improvements in activity against Gram-neg. bacteria, including pathogenic E. coli. The vancomycin-arginine conjugate (V-R) exhibited efficacy against actively growing bacteria, induced the loss of rod cellular morphol., and resulted in the intracellular accumulation of peptidoglycan precursors, all consistent with cell-wall synthesis disruption as its mechanism of action. Membrane permeabilization studies demonstrated an enhanced outer membrane permeability of V-R as compared with vancomycin. The conjugate exhibited no mammalian cell toxicity or hemolytic activity in MTT and hemolysis assays. Our study introduces a new vancomycin deriv. effective against Gram-neg. bacteria and underscores the broader potential of generating new antibiotics through combined mode-of-action and synthesis-informed design studies.
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    Vaara, M. (1992) Agents That Increase the Permeability of the Outer Membrane. Microbiol. Rev. 56 (3), 395– 411,  DOI: 10.1128/mr.56.3.395-411.1992
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    18
    Agents that increase the permeability of the outer membrane
    Vaara, Martti
    Microbiological Reviews (1992), 56 (3), 395-411CODEN: MBRED3; ISSN:0146-0749.
    A review with 241 refs. on cationic agents and chelators as outer membrane permeabilizers, the mol. mechanism of outer membrane permeability increase, and bacterial strains resistant to the permeabilizers.
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  19. 19
    Ofek, I., Cohen, S., Rahmani, R., Kabha, K., Tamarkin, D., Herzig, Y., and Rubinstein, E. (1994) Antibacterial Synergism of Polymyxin B Nonapeptide and Hydrophobic Antibiotics in Experimental Gram-Negative Infections in Mice. Antimicrob. Agents Chemother. 38 (2), 374– 377,  DOI: 10.1128/AAC.38.2.374
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    19
    Antibacterial synergism of polymyxin B nonapeptide and hydrophobic antibiotics in experimental gram-negative infections in mice
    Ofek, Izhak; Cohen, Sofie; Rahmani, Rita; Kabha, Kisra; Tamarkin, Dove; Herzig, Yaacov; Rubinstein, Ethan
    Antimicrobial Agents and Chemotherapy (1994), 38 (2), 374-7CODEN: AMACCQ; ISSN:0066-4804.
    Polymyxin B nonapeptide, derived by cleavage of the fatty acyl diaminobutryic acid from polymyxin B, is considerably less toxic, less bactericidal activity, and retains its ability to render gram-neg. bacteria susceptible to several antibiotics by permeabilizing their outer membranes. The peptide rendered all 53 polymyxin-susceptible strains tested more susceptible to novobiocin, lowering the MIC of novobiocin 8-fold or more. The combination of polymyxin B nonapeptide with novobiocin or with erythromycin administered i.p. in multiple doses synergistically protected mice infected with gram-neg. bacteria. This combination may be clin. useful because of the apparent rarity of the acquisition of resistance.
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    Velkov, T., Thompson, P. E., Nation, R. L., and Li, J. (2010) Structure--Activity Relationships of Polymyxin Antibiotics. J. Med. Chem. 53 (5), 1898– 1916,  DOI: 10.1021/jm900999h
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    Structure-Activity Relationships of Polymyxin Antibiotics
    Velkov, Tony; Thompson, Philip E.; Nation, Roger L.; Li, Jian
    Journal of Medicinal Chemistry (2010), 53 (5), 1898-1916CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review discussing the mechanisms of antibacterial activity of polymyxins, the mechanisms of resistance to polymyxins, the polymyxin-LPS complex, the synthesis of polymyxins, the structure-activity relationships of polymyxins, the polymyxin pharmacophore, and toxicol. properties of polymyxins.
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    Chiharha, S., Ito, A., Yahata, M., Tobita, T., and Koyama, Y. (1974) Chemical Synthesis, Isolation and Characterization of α-N-Fattyacyl Colistin Nonapeptide with Special Reference to the Correlation between Antimicrobial Activity and Carbon Number of Fattyacyl Moiety. Agric. Biol. Chem. 38 (3), 521– 529,  DOI: 10.1080/00021369.1974.10861184
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    Keirstead, N. D., Wagoner, M. P., Bentley, P., Blais, M., Brown, C., Cheatham, L., Ciaccio, P., Dragan, Y., Ferguson, D., Fikes, J., Galvin, M., Gupta, A., Hale, M., Johnson, N., Luo, W., McGrath, F., Pietras, M., Price, S., Sathe, A. G., Sasaki, J. C., Snow, D., Walsky, R. L., and Kern, G. (2014) Early Prediction of Polymyxin-Induced Nephrotoxicity with next-Generation Urinary Kidney Injury Biomarkers. Toxicol. Sci. 137 (2), 278– 291,  DOI: 10.1093/toxsci/kft247
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    22
    Early Prediction of Polymyxin-Induced Nephrotoxicity With Next-Generation Urinary Kidney Injury Biomarkers
    Keirstead, Natalie D.; Wagoner, Matthew P.; Bentley, Patricia; Blais, Marie; Brown, Crystal; Cheatham, Letitia; Ciaccio, Paul; Dragan, Yvonne; Ferguson, Douglas; Fikes, Jim; Galvin, Melanie; Gupta, Anshul; Hale, Michael; Johnson, Nakpangi; Luo, Wenli; McGrath, Frank; Pietras, Mark; Price, Sally; Sathe, Abhishek G.; Sasaki, Jennifer C.; Snow, Debra; Walsky, Robert L.; Kern, Gunther
    Toxicological Sciences (2014), 137 (2), 278-291CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
    Despite six decades of clin. experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of std. of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) deriv. with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathol. and biomarker anal. of PMBN, an important test of the hypothesis that fatty acid modifications and charge redns. in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathol. injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clin. stds. of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathol. evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.
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    Vaara, M. (1983) Polymyxin B Nonapeptide Complexes with Lipopolysaccharide. FEMS Microbiol. Lett. 18 (1–2), 117– 121,  DOI: 10.1111/j.1574-6968.1983.tb00461.x
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    Polymyxin B nonapeptide complexes with lipopolysaccharide
    Vaara, M.
    FEMS Microbiology Letters (1983), 18 (1-2), 117-21CODEN: FMLED7; ISSN:0378-1097.
    Polymyxin B nonapeptide (I) did not sensitize a polymyxin-resistant pmrA mutant strain of Salmonella typhimurium to the hydrophobic agents novobiocin and fusidic acid, in contrast to the parent strain, and I, like polymyxin, inhibited the biol. activities of isolated lipopolysaccharide (gelation of Limulus hemocyte lysate, consumption of complement). Apparently, I causes a disorganization of the outer membrane by binding to the acidic groups of the lipopolysaccharide, as does polymyxin.
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    Brandenburg, K., Moriyon, I., Arraiza, M. D., Lewark-Yvetot, G., Koch, M. H. J., and Seydel, U. (2002) Biophysical Investigations into the Interaction of Lipopolysaccharide with Polymyxins. Thermochim. Acta 382 (1), 189– 198,  DOI: 10.1016/S0040-6031(01)00731-6
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    Biophysical investigations into the interaction of lipopolysaccharide with polymyxins
    Brandenburg, K.; Moriyon, I.; Arraiza, M. D.; Lewark-Yvetot, G.; Koch, M. H. J.; Seydel, U.
    Thermochimica Acta (2002), 382 (1-2), 189-198CODEN: THACAS; ISSN:0040-6031. (Elsevier Science B.V.)
    It is reported on the interaction of bacterial lipopolysaccharide (LPS, endotoxin), having different sugar chain length covalently bound to its hydrophobic moiety lipid A, with the polycationic antibiotics polymyxin B (PMB) and PMB-nonapeptide (PMBN). The binding enthalpies and the lipid:peptide binding stoichiometries were detd. by isothermal titrn. calorimetry (ITC). For LPS with a long sugar chain (S: smooth form LPS from Yersinia enterocolitica), the titrn. curves exhibit a strong exo-therm which can be interpreted to result from the electrostatic interaction of the neg. charges of the LPS with the pos. charges of the peptides. In contrast, the titrn. curves of LPS with a short sugar chain (LPS Re from Escherichia coli) and of free lipid A yield complex patterns of endo- and exo-therms, which result from the superposition of electrostatic binding, fluidization of the acyl chains and a transition between different three-dimensional aggregate structures of the endo-toxins due to peptide binding. IR spectroscopy indicates that the fluidizing effect of the polymyxins is similar for both types of LPS and for lipid A. Small-angle X-ray diffraction reveals, however, that the Re-type LPS and lipid A are converted from a cubic into a multilamellar structure, whereas, the S-form LPS transforms from a unilamellar into a multilamellar structure with a small no. of lamellae. The presented data allow a better understanding of the interaction of peptides with endotoxin mols.
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    Domalaon, R., Idowu, T., Zhanel, G. G., and Schweizer, F. (2018) Antibiotic Hybrids: The Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?. Clin. Microbiol. Rev. 31 (2), e00077– 17,  DOI: 10.1128/CMR.00077-17
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    25
    Antibiotic hybrids: the next generation of agents and adjuvants against gram-negative pathogens?
    Domalaon, Ronald; Idowu, Temilolu; Zhanel, George G.; Schweizer, Frank
    Clinical Microbiology Reviews (2018), 31 (2), e00077-17/1-e00077-17/45CODEN: CMIREX; ISSN:1098-6618. (American Society for Microbiology)
    The global incidence of drug-resistant Gram-neg. bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-neg. bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-neg. bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clin. evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-neg. bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-neg. pathogens and/or expand the usefulness of our current antibiotic arsenal.
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    Duwe, A. K., Rupar, C. A., Horsman, G. B., and Vas, S. I. (1986) In Vitro Cytotoxicity and Antibiotic Activity of Polymyxin B Nonapeptide. Antimicrob. Agents Chemother. 30 (2), 340– 341,  DOI: 10.1128/AAC.30.2.340
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    In vitro cytotoxicity and antibiotic activity of polymyxin B nonapeptide
    Duwe, Axel K.; Rupar, C. Anthony; Horsman, Greg B.; Vas, Stephen I.
    Antimicrobial Agents and Chemotherapy (1986), 30 (2), 340-1CODEN: AMACCQ; ISSN:0066-4804.
    Polymyxin B nonapeptide, prepd. by enzymic removal of the fatty acyl diaminobutyric acid side chain from polymyxin B, was ∼100-fold less toxic to K562 cells than polymyxin B. Min. inhibitory concns. of polymyxin B nonapeptide against a test panel of bacteria were 2-64-fold lower than those of polymyxin B.
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    Domalaon, R., Yang, X., Lyu, Y., Zhanel, G. G., and Schweizer, F. (2017) Polymyxin B(3)-Tobramycin Hybrids with Pseudomonas Aeruginosa-Selective Antibacterial Activity and Strong Potentiation of Rifampicin, Minocycline, and Vancomycin. ACS Infect. Dis. 3 (12), 941– 954,  DOI: 10.1021/acsinfecdis.7b00145
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    27
    Polymyxin B3-Tobramycin Hybrids with Pseudomonas aeruginosa-Selective Antibacterial Activity and Strong Potentiation of Rifampicin, Minocycline, and Vancomycin
    Domalaon, Ronald; Yang, Xuan; Lyu, Yinfeng; Zhanel, George G.; Schweizer, Frank
    ACS Infectious Diseases (2017), 3 (12), 941-954CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
    There is an urgent need to develop novel antibacterial agents able to eradicate drug-resistant Gram-neg. pathogens such as Pseudomonas aeruginosa. Antimicrobial hybrids have emerged as a promising strategy to combat bacterial resistance, as a stand-alone drug but also as an adjuvant in combination with existing antibiotics. Herein, we report for the first time the synthesis and biol. evaluation of polymyxin-aminoglycoside heterodimers composed of polymyxin B3 covalently linked to tobramycin via an aliph. hydrocarbon linker. The polymyxin B3-tobramycin hybrids demonstrate potent activity against carbapenem-resistant as well as multidrug- or extensively drug-resistant (MDR/XDR) P. aeruginosa clin. isolates. Furthermore, the most potent hybrid was synergistic with currently used antibiotics against wild-type and MDR/XDR P. aeruginosa but also against Acinetobacter baumannii as well. The promising biol. activity described herein warrants addnl. studies into design and development of new antimicrobial hybrids able to surmount the problem of antimicrobial resistance.
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    Luther, A., Urfer, M., Zahn, M., Müller, M., Wang, S.-Y., Mondal, M., Vitale, A., Hartmann, J.-B., Sharpe, T., Monte, F. Lo, Kocherla, H., Cline, E., Pessi, G., Rath, P., Modaresi, S. M., Chiquet, P., Stiegeler, S., Verbree, C., Remus, T., Schmitt, M., Kolopp, C., Westwood, M.-A., Desjonquères, N., Brabet, E., Hell, S., LePoupon, K., Vermeulen, A., Jaisson, R., Rithié, V., Upert, G., Lederer, A., Zbinden, P., Wach, A., Moehle, K., Zerbe, K., Locher, H. H., Bernardini, F., Dale, G. E., Eberl, L., Wollscheid, B., Hiller, S., Robinson, J. A., and Obrecht, D. (2019) Chimeric Peptidomimetic Antibiotics against Gram-Negative Bacteria. Nature 576 (7787), 452– 458,  DOI: 10.1038/s41586-019-1665-6
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    Chimeric peptidomimetic antibiotics against Gram-negative bacteria
    Luther, Anatol; Urfer, Matthias; Zahn, Michael; Muller, Maik; Wang, Shuang-Yan; Mondal, Milon; Vitale, Alessandra; Hartmann, Jean-Baptiste; Sharpe, Timothy; Monte, Fabio Lo; Kocherla, Harsha; Cline, Elizabeth; Pessi, Gabriella; Rath, Parthasarathi; Modaresi, Seyed Majed; Chiquet, Petra; Stiegeler, Sarah; Verbree, Carolin; Remus, Tobias; Schmitt, Michel; Kolopp, Caroline; Westwood, Marie-Anne; Desjonqueres, Nicolas; Brabet, Emile; Hell, Sophie; LePoupon, Karen; Vermeulen, Annie; Jaisson, Regis; Rithie, Virginie; Upert, Gregory; Lederer, Alexander; Zbinden, Peter; Wach, Achim; Moehle, Kerstin; Zerbe, Katja; Locher, Hans H.; Bernardini, Francesca; Dale, Glenn E.; Eberl, Leo; Wollscheid, Bernd; Hiller, Sebastian; Robinson, John A.; Obrecht, Daniel
    Nature (London, United Kingdom) (2019), 576 (7787), 452-458CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    There is an urgent need for new antibiotics against Gram-neg. pathogens that are resistant to carbapenem and 3rd-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. We describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-neg. bacteria. Extensively optimized derivs. show potent activity against multidrug-resistant pathogens, including all of the Gram-neg. members of the ESKAPE pathogens. These derivs. also show favorable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclin. toxicol. studies that, if successful, will allow progress into clin. studies that have the potential to address life-threatening infections by the Gram-neg. pathogens, and thus to resolve a considerable unmet medical need.
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  29. 29
    Guan, D., Chen, F., Qiu, Y., Jiang, B., Gong, L., Lan, L., and Huang, W. (2019) Sulfonium, an Underestimated Moiety for Structural Modification, Alters the Antibacterial Profile of Vancomycin Against Multidrug-Resistant Bacteria. Angew. Chem., Int. Ed. 58 (20), 6678– 6682,  DOI: 10.1002/anie.201902210
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    29
    Sulfonium, an Underestimated Moiety for Structural Modification, Alters the Antibacterial Profile of Vancomycin Against Multidrug-Resistant Bacteria
    Guan, Dongliang; Chen, Feifei; Qiu, Yunguang; Jiang, Bofeng; Gong, Likun; Lan, Lefu; Huang, Wei
    Angewandte Chemie, International Edition (2019), 58 (20), 6678-6682CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    In the antibiotics arsenal, vancomycin is a last resort for the treatment of intractable infections. However, this situation is under threat because of the increasing appearance of vancomycin-resistant bacteria (VRB). Herein, we report a series of novel vancomycin derivs. carrying a sulfonium moiety. The sulfonium-vancomycin derivs. exhibited enhanced antibacterial activity against VRB both in vitro and in vivo. These derivs. also exhibited activity against some Gram-neg. bacteria. The sulfonium modification enhanced the interaction of vancomycin with the bacterial cell membrane and disrupts membrane integrity. Furthermore, the in vivo pharmacokinetic profile, stability, and toxicity of these derivs. demonstrated good druggability of the sulfonium-vancomycin analogs. This work provides a promising strategy for combating drug-resistant bacterial infection, and advances the knowledge on sulfonium derivs. for structural optimization and drug development.
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  30. 30
    Shi, W., Chen, F., Zou, X., Jiao, S., Wang, S., Hu, Y., Lan, L., Tang, F., and Huang, W. (2021) Design, Synthesis, and Antibacterial Evaluation of Vancomycin-LPS Binding Peptide Conjugates. Bioorg. Med. Chem. Lett. 45, 128122,  DOI: 10.1016/j.bmcl.2021.128122
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    Design, synthesis, and antibacterial evaluation of vancomycin-LPS binding peptide conjugates
    Shi, Weiwei; Chen, Feifei; Zou, Xiangman; Jiao, Shang; Wang, Siqi; Hu, Yu; Lan, Lefu; Tang, Feng; Huang, Wei
    Bioorganic & Medicinal Chemistry Letters (2021), 45 (), 128122CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Developing novel antibiotics is urgently needed with emergency of drug resistance. Vancomycin, the last resort for intractable Gram-pos. bacterial infections, is ineffective against Gram-neg. bacteria and vancomycin resistant bacteria. Herein, we report a series of novel vancomycin derivs. carrying LPS binding peptides, vancomycin-LPS binding peptide conjugates (VPCs). The LPS binding peptides were conjugated onto 4 sites of vancomycin via CuAAC or maleimide- sulfydryl addn., and the formed VPCs were screened against VISA/VRE and Gram-neg. strains. VPCs exhibited enhanced activity against vancomycin resistant bacteria and obtained the activity against Gram-neg. bacteria in vitro, providing a novel strategy for vancomycin modification and glycopeptide antibiotics synthesis.
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    Yarlagadda, V., Akkapeddi, P., Manjunath, G. B., and Haldar, J. (2014) Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance. J. Med. Chem. 57 (11), 4558– 4568,  DOI: 10.1021/jm500270w
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    Membrane active vancomycin analogs: a strategy to combat bacterial resistance
    Yarlagadda, Venkateswarlu; Akkapeddi, Padma; Manjunath, Goutham B.; Haldar, Jayanta
    Journal of Medicinal Chemistry (2014), 57 (11), 4558-4568CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The alarming growth of antibiotic-resistant superbugs such as vancomycin-resistant enterococci and staphylococci has become a major global health hazard. To address this issue, the authors report the development of lipophilic cationic vancomycin analogs possessing excellent antibacterial activity against several drug-resistant strains. Compared to vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant Enterococci (VRE). Significantly, unlike vancomycin, these compds. were shown to be bactericidal at low concns. and did not induce bacterial resistance. An optimized compd. in the series, compared to vancomycin, showed higher activity in methicillin-resistant Staphylococcus aureus (MRSA) infected mouse model and exhibited superior antibacterial activity in whole blood with no obsd. toxicity. The remarkable activity of these compds. is attributed to the incorporation of a new membrane disruption mechanism into vancomycin and opens up a great opportunity for the development of novel antibiotics.
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    Okano, A., Isley, N. A., and Boger, D. L. (2017) Peripheral Modifications of [Ψ[CH2NH]Tpg4]Vancomycin with Added Synergistic Mechanisms of Action Provide Durable and Potent Antibiotics. Proc. Natl. Acad. Sci. U. S. A. 114, 5052– 5061,  DOI: 10.1073/pnas.1704125114
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    Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics
    Okano, Akinori; Isley, Nicholas A.; Boger, Dale L.
    Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (26), E5052-E5061CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Subsequent to binding pocket modifications designed to provide dual d-Ala-d-Ala/d-Ala-d-Lac binding that directly overcome the mol. basis of vancomycin resistance, peripheral structural changes have been explored to improve antimicrobial potency and provide addnl. synergistic mechanisms of action. A C-terminal peripheral modification, introducing a quaternary ammonium salt, is reported and was found to provide a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of d-Ala-d-Ala/d-Ala-d-Lac binding. This modification, which induces cell wall permeability and is complementary to the glycopeptide inhibition of cell wall synthesis, was found to provide improvements in antimicrobial potency (200-fold) against vancomycin-resistant Enterococci (VRE). Furthermore, it is shown that this type of C-terminal modification may be combined with a second peripheral (4-chlorobiphenyl)methyl (CBP) addn. to the vancomycin disaccharide to provide even more potent antimicrobial agents [VRE min. inhibitory concn. (MIC) = 0.01-0.005 μg/mL] with activity that can be attributed to three independent and synergistic mechanisms of action, only one of which requires d-Ala-d-Ala/d-Ala-d-Lac binding. Finally, it is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by VRE and that their durability against such challenges as well as their antimicrobial potency follow now predictable trends (three > two > one mechanisms of action). Such antibiotics are expected to display durable antimicrobial activity not prone to rapidly acquired clin. resistance.
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    Blaskovich, M. A. T., Hansford, K. A., Gong, Y., Butler, M. S., Muldoon, C., Huang, J. X., Ramu, S., Silva, A. B., Cheng, M., Kavanagh, A. M., Ziora, Z., Premraj, R., Lindahl, F., Bradford, T. A., Lee, J. C., Karoli, T., Pelingon, R., Edwards, D. J., Amado, M., Elliott, A. G., Phetsang, W., Daud, N. H., Deecke, J. E., Sidjabat, H. E., Ramaologa, S., Zuegg, J., Betley, J. R., Beevers, A. P. G., Smith, R. A. G., Roberts, J. A., Paterson, D. L., and Cooper, M. A. (2018) Protein-Inspired Antibiotics Active against Vancomycin- and Daptomycin-Resistant Bacteria. Nat. Commun. 9 (1), 1– 17,  DOI: 10.1038/s41467-017-02123-w
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    Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria
    Blaskovich, Mark A. T.; Hansford, Karl A.; Gong, Yujing; Butler, Mark S.; Muldoon, Craig; Huang, Johnny X.; Ramu, Soumya; Silva, Alberto B.; Cheng, Mu; Kavanagh, Angela M.; Ziora, Zyta; Premraj, Rajaratnam; Lindahl, Fredrik; Bradford, Tanya A.; Lee, June C.; Karoli, Tomislav; Pelingon, Ruby; Edwards, David J.; Amado, Maite; Elliott, Alysha G.; Phetsang, Wanida; Daud, Noor Huda; Deecke, Johan E.; Sidjabat, Hanna E.; Ramaologa, Sefetogi; Zuegg, Johannes; Betley, Jason R.; Beevers, Andrew P. G.; Smith, Richard A. G.; Roberts, Jason A.; Paterson, David L.; Cooper, Matthew A.
    Nature Communications (2018), 9 (1), 1-17CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biol. pathways via modulation of membrane-assocd. proteins and membrane lipid compn. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on pos. charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-pos. bacteria, and retain activity against glycopeptide-resistant strains. Optimized antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other i.v.-administered drugs that target membrane-assocd. receptors.
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    Wu, Z.-C., Cameron, M. D., and Boger, D. L. (2020) Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification. ACS Infect. Dis. 6 (8), 2169– 2180,  DOI: 10.1021/acsinfecdis.0c00258
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    Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification
    Wu, Zhi-Chen; Cameron, Michael D.; Boger, Dale L.
    ACS Infectious Diseases (2020), 6 (8), 2169-2180CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
    A series of vancomycin C-terminus guanidine modifications is disclosed that improves antimicrobial activity, enhances the durability of antimicrobial action against selection or induction of resistance, and introduces a synergistic mechanism of action independent of D-Ala-D-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compds. examd. that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive but esp. vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of D-Ala-D-Ala/D-Lac binding and display superb antimicrobial potencies (MIC 0.6-0.15 μg/mL, VanA VRE). For the first time, we demonstrate that the synergistic behavior of the peripheral modifications examd. requires the presence of both the CBP and guanidine modifications in a single mol. vs. their combined use as an equimolar mixt. of singly modified compds. Finally, we show that a prototypical member of the series, G3-CBP-vancomycin (15), exhibits no hemolytic activity, displays no mammalian cell growth inhibition, possesses improved and esp. attractive in vivo pharmacokinetic (PK) properties, and displays excellent in vivo efficacy and potency against an esp. challenging multidrug-resistant (MRSA) and VanA vancomycin-resistant (VRSA) Staphylococcus aureus bacterial strain.
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    Sarkar, P., Basak, D., Mukherjee, R., Bandow, J. E., and Haldar, J. Alkyl-Aryl-Vancomycins: Multimodal Glycopeptides with Weak Dependence on the Bacterial Metabolic State. J. Med. Chem. 2021 64 (14), 10185− 10202 DOI: 10.1021/acs.jmedchem.1c00449
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    Alkyl-Aryl-Vancomycins: Multimodal Glycopeptides with Weak Dependence on the Bacterial Metabolic State
    Sarkar, Paramita; Basak, Debajyoti; Mukherjee, Riya; Bandow, Julia E.; Haldar, Jayanta
    Journal of Medicinal Chemistry (2021), 64 (14), 10185-10202CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Resistance to last-resort antibiotics such as vancomycin for Gram-pos. bacterial infections necessitates the development of new therapeutics. Furthermore, the ability of bacteria to survive antibiotic therapy through formation of biofilms and persister cells complicates treatment. Toward this, we report alkyl-aryl-vancomycins (AAVs), with high potency against vancomycin-resistant enterococci and staphylococci. Unlike vancomycin, the lead compd. AAV-qC10 was bactericidal and weakly dependent on bacterial metab. This resulted in complete eradication of non-growing cells of MRSA and disruption of its biofilms. In addn. to inhibiting cell wall biosynthesis like vancomycin, AAV-qC10 also depolarizes and permeabilizes the membrane. More importantly, the compd. delocalized the cell division protein MinD, thereby impairing bacterial growth through multiple pathways. The potential of AAV-qC10 is exemplified by its superior efficacy against MRSA in a murine thigh infection model as compared to vancomycin. This work paves the way for structural optimization and drug development for combating drug-resistant bacterial infections.
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    Rostovtsev, V. V., Green, L. G., Fokin, V. V., and Sharpless, K. B. (2002) A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem., Int. Ed. 41 (14), 2596– 2599,  DOI: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4
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    A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes
    Rostovtsev, Vsevolod V.; Green, Luke G.; Fokin, Valery V.; Sharpless, K. Barry
    Angewandte Chemie, International Edition (2002), 41 (14), 2596-2599CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
    1,4-Disubstituted 1,2,3-triazoles I (R1 = PhCH2, PhCH2OCH2, 1-adamantyl, etc.; R2 = HO2C, Ph, PhOCH2, Et2NCH2, etc.) were readily and cleanly prepd. via highly efficient and regioselective copper(I)-catalyzed cycloaddn. of azides R1N3 with terminal alkynes R2C≡CH in 82-93% yields.
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    Tornøe, C. W., Christensen, C., and Meldal, M. (2002) Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 67 (9), 3057– 3064,  DOI: 10.1021/jo011148j
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    Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides
    Tornoe, Christian W.; Christensen, Caspar; Meldal, Morten
    Journal of Organic Chemistry (2002), 67 (9), 3057-3064CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    The cycloaddn. of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. This work reports a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddn. of terminal alkynes to azides on solid-phase. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddn. producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the x-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides were prepd. from Fmoc-amino alcs. by Mitsunobu reaction.
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    Silverman, S. M., Moses, J. E., and Sharpless, K. B. (2017) Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE. Chem. - Eur. J. 23 (1), 79– 83,  DOI: 10.1002/chem.201604765
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    Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE
    Silverman, Steven M.; Moses, John E.; Sharpless, K. Barry
    Chemistry - A European Journal (2017), 23 (1), 79-83CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Vancomycin has long been considered a drug of last resort. Its efficiency in treating multiple drug-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), has had a profound effect on the treatment of life-threatening infections. However, the emergence of resistance to vancomycin is a cause for significant worldwide concern, prompting the urgent development of new effective treatments for antibiotic resistant bacterial infections. Harnessing the benefits of multivalency and cooperativity against vancomycin-resistant strains, we report a Click Chem. approach towards reengineered vancomycin derivs. and the synthesis of a no. of dimers with increased potency against MRSA and vancomycin resistant Enterococci (VRE; VanB). These semi-synthetic dimeric ligands were linked together with great efficiency using the powerful CuAAC reaction, demonstrating high levels of selectivity and purity.
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    O’Dowd, H., Kim, B., Margolis, P., Wang, W., Wu, C., Lopez, S. L., and Blais, J. (2007) Preparation of Tetra-Boc-Protected Polymyxin B Nonapeptide. Tetrahedron Lett. 48 (11), 2003– 2005,  DOI: 10.1016/j.tetlet.2007.01.071
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    Preparation of tetra-Boc-protected polymyxin B nonapeptide
    O'Dowd, Hardwin; Kim, Bum; Margolis, Peter; Wang, Wen; Wu, Charlotte; Lopez, Sara L.; Blais, Johanne
    Tetrahedron Letters (2007), 48 (11), 2003-2005CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    A method for the selective tetra-Boc-protection of polymyxin B nonapeptide (PMBN) has been developed. Boc-ON selectively protects the amino side chains of the four diaminobutyric acid (Dab) residues in the presence of the N-terminal free amine.
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    Chevalier, S., Bouffartigues, E., Bodilis, J., Maillot, O., Lesouhaitier, O., Feuilloley, M. G. J., Orange, N., Dufour, A., and Cornelis, P. (2017) Structure, Function and Regulation of Pseudomonas Aeruginosa Porins. FEMS Microbiol. Rev. 41 (5), 698– 722,  DOI: 10.1093/femsre/fux020
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    Structure, function and regulation of Pseudomonas aeruginosa porins
    Chevalier, Sylvie; Bouffartigues, Emeline; Bodilis, Josselin; Maillot, Olivier; Lesouhaitier, Olivier; Feuilloley, Marc G. J.; Orange, Nicole; Dufour, Alain; Cornelis, Pierre
    FEMS Microbiology Reviews (2017), 41 (5), 698-722CODEN: FMREE4; ISSN:1574-6976. (Oxford University Press)
    A review. Pseudomonas aeruginosa is a Gram-neg. bacterium belonging to the γ -proteobacteria. Like other members of the Pseudomonas genus, it is known for its metabolic versatility and its ability to colonize a wide range of ecol. niches, such as rhizosphere, water environments and animal hosts, including humans where it can cause severe infections. Another particularity of P. aeruginosa is its high intrinsic resistance to antiseptics and antibiotics, which is partly due to its low outer membrane permeability. In contrast to Enterobacteria, pseudomonads do not possess general diffusion porins in their outer membrane, but rather express specific channel proteins for the uptake of different nutrients. The major outer membrane 'porin', OprF, has been extensively investigated, and displays structural, adhesion and signaling functions while its role in the diffusion of nutrients is still under discussion. Other porins include OprB and OprB2 for the diffusion of glucose, the two small outer membrane proteins OprG and OprH, and the two porins involved in phosphate/pyrophosphate uptake, OprP and OprO. The remaining nineteen porins belong to the so-called OprD (Occ) family, which is further split into two subfamilies termed OccD (8 members) and OccK (11 members). In the past years, a large amt. of information concerning the structure, function and regulation of these porins has been published, justifying why an updated review is timely.
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    Moore, R. A., Bates, N. C., and Hancock, R. E. (1986) Interaction of Polycationic Antibiotics with Pseudomonas Aeruginosa Lipopolysaccharide and Lipid A Studied by Using Dansyl-Polymyxin. Antimicrob. Agents Chemother. 29 (3), 496– 500,  DOI: 10.1128/AAC.29.3.496
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    Interaction of polycationic antibiotics with Pseudomonas aeruginosa lipopolysaccharide and lipid A studied by using dansyl-polymyxin
    Moore, Richard A.; Bates, Nancy C.; Hancock, Robert E. W.
    Antimicrobial Agents and Chemotherapy (1986), 29 (3), 496-500CODEN: AMACCQ; ISSN:0066-4804.
    A fluorescent deriv. of polymyxin B (dansyl-polymyxin) was used to study the interaction of polycations with lipopolysaccharide (LPS) and lipid A from P. aeruginosa. Dansyl-polymyxin became bound to LPS and lipid A sites, including Mg2+-binding sites, resulting in a 20-fold enhancement of fluorescence. A Hill plot of the binding data showed that the binding of dansyl-polymyxin to LPS was cooperative (n = 1.98) and of high affinity (S0.5 = 0.38 μM). The maximal binding capacity of LPS was ∼4 mol of dansyl-polymyxin/mol of LPS. The dansyl-polymyxin interaction with lipid A displayed similar kinetics (n = 2.26; S0.5 = 0.38 μM), and the maximal binding capacity was ∼2 mol of dansyl-polymyxin/mol lipid A. A variety of polycationic compds., including gentamicin, streptomycin, and polymyxin B, as well as Mg2+, were able to displace dansyl-polymyxin bound to LPS or to lipid A. Marked differences both in terms of the degree of displacement and in terms of the amt. of competing polycation required to displace a given amt. of dansyl-polymyxin were obsd. Addn. of excess polymyxin B resulted in displacement of all of the dansyl-polymyxin, demonstrating that only polymyxin-binding sites were being probed. Apparently, polymyxin B binds to multiple sites on LPS, including sites which bind aminoglycoside antibiotics and other polycationic compds.
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  • Abstract

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    Figure 1

    Figure 1. Structures of clinically used antibiotics vancomycin and colistin (polymyxin E), with the colistin-derived polymyxin E nonapeptide (PMEN) also indicated.

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    Scheme 1

    Scheme 1. Vancomyxins Prepared in Present Studya
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    aReagents and conditions used: (i) CuSO4 pentahydrate, sodium ascorbate, H2O.

    Figure 2

    Figure 2. Structures of the vancomyxins 11, 14, and 15 with ionization state at neutral pH.

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  • References

    This article references 49 other publications.

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      Blaskovich, M. A. T., Hansford, K. A., Butler, M. S., Jia, Z., Mark, A. E., and Cooper, M. A. (2018) Developments in Glycopeptide Antibiotics. ACS Infect. Dis. 4, 715– 735,  DOI: 10.1021/acsinfecdis.7b00258
      4
      Developments in Glycopeptide Antibiotics
      Blaskovich, Mark A. T.; Hansford, Karl A.; Butler, Mark S.; Jia, ZhiGuang; Mark, Alan E.; Cooper, Matthew A.
      ACS Infectious Diseases (2018), 4 (5), 715-735CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      A review. Glycopeptide antibiotics (GPA) are a key weapon in the fight against drug resistant bacteria, with vancomycin still a mainstream therapy against serious Gram-pos. infections more than 50 years after it was first introduced. New, more potent semisynthetic derivs. that have entered the clinic, such as dalbavancin and oritavancin, have superior pharmacokinetic and target engagement profiles that enable successful treatment of vancomycin-resistant infections. In the face of resistance development, with multi-drug resistant (MDR) S. pneumonia and MRSA together causing 20-fold more infections than all MDR Gram-neg. infections combined, further improvements are desirable to ensure the Gram-pos. armamentarium is adequately maintained for future generations. A range of modified glycopeptides has been generated in the last decade via total syntheses, semisynthetic modifications of a natural product or biol. engineering. Several of these have undergone extensive characterization with demonstrated in vivo efficacy, good PK/PD profiles and no reported pre-clin. toxicity; some may be suitable for formal preclin. development. The natural product monobactam, cephalosporin and beta-lactam antibiotics all spawned multiple generations of com. and clin. successful semi-synthetic derivs. Similarly, next-generation glycopeptides are now tech. well positioned to advance to the clinic, if sufficient funding and market support returns to antibiotic development.
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    5. 5
      Mackay, J. P., Gerhard, U., Beauregard, D. A., Williams, D. H., Westwell, M. S., and Searle, M. S. (1994) Glycopeptide Antibiotic Activity and the Possible Role of Dimerization: A Model for Biological Signaling. J. Am. Chem. Soc. 116 (11), 4581– 4590,  DOI: 10.1021/ja00090a006
      5
      Glycopeptide Antibiotic Activity and the Possible Role of Dimerization: A Model for Biological Signaling
      Mackay, Joel P.; Gerhard, Ute; Beauregard, Daniel A.; Williams, Dudley H.; Westwell, Martin S.; Searle, Mark S.
      Journal of the American Chemical Society (1994), 116 (11), 4581-90CODEN: JACSAT; ISSN:0002-7863.
      It is demonstrated that the presence of bacterial cell wall analogs may either enhance or, in the case of ristocetin A, oppose dimerization of glycopeptide antibiotics. These observations may imply that dimerization plays a role in the mode of action of these antibiotics, and a mechanism is proposed to take account of this possibility. The glycopeptide dimers are also found to be formed more exothermically in the presence of cell wall analogs, and the nature of biol. signaling events is discussed in this context. It is pointed out that binding enthalpy (rather than simply binding free energy, ΔG) may be an important quantity in signaling events. If this is so, then oligomers may be abundant in signaling processes partly because the extended aggregates they form are able to cooperatively amplify the conformational changes which are incurred on ligand binding, which occur through relatively small changes in free energy but larger opposing changes in enthalpy and entropy.
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    6. 6
      Shlaes, D. M., Shlaes, J. H., Davies, J., and Williamson, R. (1989) Escherichia Coli Susceptible to Glycopeptide Antibiotics. Antimicrob. Agents Chemother. 33 (2), 192– 197,  DOI: 10.1128/AAC.33.2.192
      6
      Escherichia coli susceptible to glycopeptide antibiotics
      Shlaes, David M.; Shlaes, Janet H.; Davies, Julian; Williamson, Russell
      Antimicrobial Agents and Chemotherapy (1989), 33 (2), 192-7CODEN: AMACCQ; ISSN:0066-4804.
      Mutants of E. coli susceptible to vancomycin were isolated after mutagenesis with nitrosoguanidine. One such mutant was studied extensively. Multiple regression anal. of the relationship between phys. properties of 20 glycopeptides and their in vitro activities against the vancomycin-susceptible mutant revealed a significant correlation with mol. mass. PI, hydrophobicity, and affinity of the glycopeptide for the pentapeptide target were not as important for activity. This suggested that a block of access of the antibiotic to its target could be the major factor detg. activity. Outer membrane proteins of the vancomycin-susceptible mutant, resistant parent, and revertant strains appeared normal. The mutant exhibited increased susceptibility to both erythromycin and fusidic acid which was lost in single-step revertants to vancomycin resistance. Polymyxin B nonapeptide was synergistic with erythromycin and fusidic acid against the parent and revertant but not against the susceptible mutant. Anal. of the susceptibilities of control strains of E. coli and Salmonella thyphimurium with known defects in lipopolysaccharide (LPS) synthesis revealed that core LPS mutants (Re chemotype) were phenotypically similar to the E. coli mutant under study. However, the LPS core of the mutant migrated slightly less rapidly on SDS-PAGE than wild-type or revertant core LPS and did not resemble Re chemotype LPS core obtained from Salmonella rfaC and rfaD mutants. These data suggest that defects in LPS core structure other than loss of heptose moieties may also be important in loss of resistance to large, hydrophilic mols. such as glycopeptides.
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    7. 7
      Henderson, J. C., Zimmerman, S. M., Crofts, A. A., Boll, J. M., Kuhns, L. G., Herrera, C. M., and Trent, M. S. (2016) The Power of Asymmetry: Architecture and Assembly of the Gram-Negative Outer Membrane Lipid Bilayer. Annu. Rev. Microbiol. 70 (1), 255– 278,  DOI: 10.1146/annurev-micro-102215-095308
      7
      The Power of Asymmetry: Architecture and Assembly of the Gram-Negative Outer Membrane Lipid Bilayer
      Henderson, Jeremy C.; Zimmerman, Shawn M.; Crofts, Alexander A.; Boll, Joseph M.; Kuhns, Lisa G.; Herrera, Carmen M.; Trent, M. Stephen
      Annual Review of Microbiology (2016), 70 (), 255-278CODEN: ARMIAZ; ISSN:0066-4227. (Annual Reviews)
      Detg. the chem. compn. of biol. materials is paramount to the study of natural phenomena. Here, we describe the compn. of model gram-neg. outer membranes, focusing on the predominant assembly, an asym. bilayer of lipid mols. We also give an overview of lipid biosynthetic pathways and mol. mechanisms that organize this material into the outer membrane bilayer. An emphasis is placed on the potential of these pathways as targets for antibiotic development. We discuss deviations in compn., through bacterial cell surface remodeling, and alternative modalities to the asym. lipid bilayer. Outer membrane lipid alterations of current microbiol. interest, such as lipid structures found in commensal bacteria, are emphasized. Addnl., outer membrane components could potentially be engineered to develop vaccine platforms. Observations related to compn. and assembly of gram-neg. outer membranes will continue to generate novel discoveries, broaden biotechnologies, and reveal profound mysteries to compel future research.
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    8. 8
      Heesterbeek, D. A. C., Martin, N. I., Velthuizen, A., Duijst, M., Ruyken, M., Wubbolts, R., Rooijakkers, S. H. M., and Bardoel, B. W. (2019) Complement-Dependent Outer Membrane Perturbation Sensitizes Gram-Negative Bacteria to Gram-Positive Specific Antibiotics. Sci. Rep. 9 (1), 3074
      8
      Complement-dependent outer membrane perturbation sensitizes Gram-negative bacteria to Gram-positive specific antibiotics
      Heesterbeek D A C; Velthuizen A; Duijst M; Ruyken M; Rooijakkers S H M; Bardoel B W; Martin N I; Wubbolts R
      Scientific reports (2019), 9 (1), 3074 ISSN:.
      Gram-negative bacteria are refractory to the action of many antibiotics due to their impermeable outer membrane. An important player of the immune system is the complement system, a protein network in serum that directly kills Gram-negative bacteria through pore-formation by the Membrane Attack Complexes (MAC). We here show that the MAC rapidly perforates the outer membrane but that inner membrane damage, which is essential for killing, is relatively slow. Importantly, we demonstrate that MAC-induced outer membrane damage sensitizes Gram-negative bacteria to otherwise ineffective, Gram-positive-specific, antimicrobials. Synergy between serum and nisin was observed for 22 out of 53 tested Gram-negative clinical isolates and for multi-drug resistant (MDR) blood isolates. The in vivo relevance of this process is further highlighted by the fact that blood sensitizes a MDR K. pneumoniae strain to vancomycin. Altogether, these data imply that antibiotics that are considered ineffective to treat infections with Gram-negatives may have different functional outcomes in patients, due to the presence of the complement system.
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    9. 9
      Stokes, J. M., MacNair, C. R., Ilyas, B., French, S., Côté, J.-P., Bouwman, C., Farha, M. A., Sieron, A. O., Whitfield, C., Coombes, B. K., and Brown, E. D. (2017) Pentamidine Sensitizes Gram-Negative Pathogens to Antibiotics and Overcomes Acquired Colistin Resistance. Nat. Microbiol. 2, 17028,  DOI: 10.1038/nmicrobiol.2017.28
      9
      Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance
      Stokes Jonathan M; MacNair Craig R; Ilyas Bushra; French Shawn; Cote Jean-Philippe; Farha Maya A; Sieron Arthur O; Coombes Brian K; Brown Eric D; Bouwman Catrien; Whitfield Chris
      Nature microbiology (2017), 2 (), 17028 ISSN:.
      The increasing use of polymyxins(1) in addition to the dissemination of plasmid-borne colistin resistance threatens to cause a serious breach in our last line of defence against multidrug-resistant Gram-negative pathogens, and heralds the emergence of truly pan-resistant infections. Colistin resistance often arises through covalent modification of lipid A with cationic residues such as phosphoethanolamine-as is mediated by Mcr-1 (ref. 2)-which reduce the affinity of polymyxins for lipopolysaccharide(3). Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections(4). The difficulty in eradicating Gram-negative bacteria is largely due to their highly impermeable outer membrane, which serves as a barrier to many otherwise effective antibiotics(5). Here, we describe an unconventional screening platform designed to enrich for non-lethal, outer-membrane-active compounds with potential as adjuvants for conventional antibiotics. This approach identified the antiprotozoal drug pentamidine(6) as an effective perturbant of the Gram-negative outer membrane through its interaction with lipopolysaccharide. Pentamidine displayed synergy with antibiotics typically restricted to Gram-positive bacteria, yielding effective drug combinations with activity against a wide range of Gram-negative pathogens in vitro, and against systemic Acinetobacter baumannii infections in mice. Notably, the adjuvant activity of pentamidine persisted in polymyxin-resistant bacteria in vitro and in vivo. Overall, pentamidine and its structural analogues represent unexploited molecules for the treatment of Gram-negative infections, particularly those having acquired polymyxin resistance determinants.
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    10. 10
      Li, Q., Cebrián, R., Montalbán-López, M., Ren, H., Wu, W., and Kuipers, O. P. (2021) Outer-Membrane-Acting Peptides and Lipid II-Targeting Antibiotics Cooperatively Kill Gram-Negative Pathogens. Commun. Biol. 4 (1), 31,  DOI: 10.1038/s42003-020-01511-1
      10
      Outer-membrane-acting peptides and lipid II-targeting antibiotics cooperatively kill Gram-negative pathogens
      Li, Qian; Cebrian, Ruben; Montalban-Lopez, Manuel; Ren, Huan; Wu, Weihui; Kuipers, Oscar P.
      Communications Biology (2021), 4 (1), 31CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)
      The development and dissemination of antibiotic-resistant bacterial pathogens is a growing global threat to public health. Novel compds. and/or therapeutic strategies are required to face the challenge posed, in particular, by Gram-neg. bacteria. Here we assess the combined effect of potent cell-wall synthesis inhibitors with either natural or synthetic peptides that can act on the outer-membrane. Thus, several linear peptides, either alone or combined with vancomycin or nisin, were tested against selected Gram-neg. pathogens, and the best one was improved by further engineering. Finally, peptide D-11 and vancomycin displayed a potent antimicrobial activity at low μM concns. against a panel of relevant Gram-neg. pathogens. This combination was highly active in biol. fluids like blood, but was non-hemolytic and non-toxic against cell lines. We conclude that vancomycin and D-11 are safe at >50-fold their MICs. Based on the results obtained, and as a proof of concept for the newly obsd. synergy, a Pseudomonas aeruginosa mouse infection model expt. was also performed, showing a 4 log10 redn. of the pathogen after treatment with the combination. This approach offers a potent alternative strategy to fight (drug-resistant) Gram-neg. pathogens in humans and mammals.
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    11. 11
      Ghosh, M., Lin, Y.-M., Miller, P. A., Möllmann, U., Boggess, W. C., and Miller, M. J. (2018) Siderophore Conjugates of Daptomycin Are Potent Inhibitors of Carbapenem Resistant Strains of Acinetobacter Baumannii. ACS Infect. Dis. 4 (10), 1529– 1535,  DOI: 10.1021/acsinfecdis.8b00150
      11
      Siderophore Conjugates of Daptomycin are Potent Inhibitors of Carbapenem Resistant Strains of Acinetobacter baumannii
      Ghosh, Manuka; Lin, Yun-Ming; Miller, Patricia A.; Mollmann, Ute; Boggess, William C.; Miller, Marvin J.
      ACS Infectious Diseases (2018), 4 (10), 1529-1535CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      Development of resistance to antibiotics is a major medical problem. One approach to extending the utility of our limited antibiotic arsenal is to repurpose antibiotics by altering their bacterial selectivity. Many antibiotics that are used to treat infections caused by Gram-pos. bacteria might be made effective against Gram-neg. bacterial infections, if they could circumvent permeability barriers and antibiotic deactivation processes assocd. with Gram-neg. bacteria. Herein, we report that covalent attachment of the normally Gram-pos.-only antibiotic, daptomycin, with iron sequestering siderophore mimetics that are recognized by Gram-neg. bacteria, provides conjugates that are active against virulent strains of Acinetobacter baumannii, including carbapenemase and cephalosporinase producers. The result is the generation of a new set of antibiotics designed to target bacterial infections that have been designated as being of dire concern.
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    12. 12
      Li, X.-Z., Plésiat, P., and Nikaido, H. (2015) The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria. Clin. Microbiol. Rev. 28 (2), 337– 418,  DOI: 10.1128/CMR.00117-14
      12
      The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria
      Li, Xian-Zhi; Plesiat, Patrick; Nikaido, Hiroshi
      Clinical Microbiology Reviews (2015), 28 (2), 337-418CODEN: CMIREX; ISSN:1098-6618. (American Society for Microbiology)
      The global emergence of multidrug-resistant Gram-neg. bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clin. relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Addnl., efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technol. advances have allowed for an in-depth understanding of the structural and biochem. basis, substrate profiles, mol. regulation, and inhibition of MDR pumps. However, the development of clin. useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clin. significance, together with methodol. considerations for the characterization of MDR pumps.
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    13. 13
      Zabawa, T. P., Pucci, M. J., Parr, T. R., and Lister, T. (2016) Treatment of Gram-Negative Bacterial Infections by Potentiation of Antibiotics. Curr. Opin. Microbiol. 33, 7– 12,  DOI: 10.1016/j.mib.2016.05.005
      13
      Treatment of Gram-negative bacterial infections by potentiation of antibiotics
      Zabawa, Thomas P.; Pucci, Michael J.; Parr, Thomas R.; Lister, Troy
      Current Opinion in Microbiology (2016), 33 (), 7-12CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)
      Infections caused by antibiotic-resistant pathogens, particularly Gram-neg. bacteria, represent significant treatment challenges for physicians resulting in high rates of morbidity and mortality. The outer membrane of Gram-neg. bacteria acts as a permeability barrier to many compds. that would otherwise be effective antibacterial agents, including those effective against Gram-pos. pathogens. Potentiator mols. disrupt this barrier allowing entry of otherwise impermeant mols., thus providing a strategy to render multi-drug resistant pathogens susceptible to a broader range of antibiotics. Potentiator mols. are cationic and the mechanism of disruption involves interaction with the neg. charged outer membrane. This phys. attribute, along with an often high degree of lipophilicity typically endears these mols. with unacceptable toxicity. Presented herein are examples of advanced potentiator mols. being evaluated for use in combination therapy for the treatment of resistant Gram-neg. infections.
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    14. 14
      Ghosh, M. and Miller, M. J. (1996) Synthesis and in Vitro Antibacterial Activity of Spermidine-Based Mixed Catechol- and Hydroxamate-Containing Siderophore--Vancomycin Conjugates. Bioorg. Med. Chem. 4 (1), 43– 48,  DOI: 10.1016/0968-0896(95)00161-1
      14
      Synthesis and in vitro antibacterial activity of spermidine-based mixed catechol- and hydroxamate-containing siderophore-vancomycin conjugates
      Ghosh, Manuka; Miller, Marvin J.
      Bioorganic & Medicinal Chemistry (1996), 4 (1), 43-8CODEN: BMECEP; ISSN:0968-0896. (Elsevier)
      The first antibiotic conjugates of vancomycin with siderophore analogs contg. spermidine-based catechol ligands or mixed catechol and hydroxamate ligands are described. The design of the conjugates was based on the earlier observation that conjugation of siderophore components to β-lactam antibiotics induced active iron transport-mediated drug delivery. The novel conjugates were synthesized by selective acylation of the primary amino group of vancomycin. Preliminary biol. studies indicted that siderophore modified vancomycins lost some activity (4- to 16-fold) against Gram-pos. bacteria relative to vancomycin itself, and were generally similar to vancomycin in activity against Gram-neg. bacteria under iron-sufficient conditions. However, under iron-depleted conditions which mimic human serum, the conjugate contg. the spermidine-based catechol ligand displayed enhanced antibacterial activity against an antibiotic hypersensitive strain of Pseudomonas aeruginosa.
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    15. 15
      Sarkar, P., Samaddar, S., Ammanathan, V., Yarlagadda, V., Ghosh, C., Shukla, M., Kaul, G., Manjithaya, R., Chopra, S., and Haldar, J. (2020) Vancomycin Derivative Inactivates Carbapenem-Resistant Acinetobacter Baumannii and Induces Autophagy. ACS Chem. Biol. 15 (4), 884– 889,  DOI: 10.1021/acschembio.0c00091
      15
      Vancomycin Derivative Inactivates Carbapenem-Resistant Acinetobacter baumannii and Induces Autophagy
      Sarkar, Paramita; Samaddar, Sandip; Ammanathan, Veena; Yarlagadda, Venkateswarlu; Ghosh, Chandradhish; Shukla, Manjulika; Kaul, Grace; Manjithaya, Ravi; Chopra, Sidharth; Haldar, Jayanta
      ACS Chemical Biology (2020), 15 (4), 884-889CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      Vancomycin is a std. drug for the treatment of multidrug-resistant Gram-pos. bacterial infections. Albeit, development of resistance (VRE, VRSA) and its inefficacy against persistent infections is a demerit. It is also intrinsically inactive against Gram-neg. bacteria. Herein, we report a vancomycin deriv., VanQAmC10, that addresses these challenges. VanQAmC10 was rapidly bactericidal against carbapenem-resistant A. baumannii (6 log10 CFU/mL redn. in 6 h), disrupted A. baumannii biofilms, and eradicated their stationary phase cells. In MRSA infected macrophages, the compd. reduced the bacterial burden by 1.3 log10 CFU/mL while vancomycin exhibited a static effect. Further investigation indicated that the compd., unlike vancomycin, promoted the intracellular degradative mechanism, autophagy, in mammalian cells, which may have contributed to its intracellular activity. The findings of the work provide new perspectives on the field of glycopeptide antibiotics.
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    16. 16
      Neville, L. F., Shalit, I., Warn, P. A., Scheetz, M. H., Sun, J., Chosy, M. B., Wender, P. A., Cegelski, L., and Rendell, J. T. (2021) In Vivo Targeting of Escherichia Coli with Vancomycin-Arginine. Antimicrob. Agents Chemother. 65 (4), e02416– 20,  DOI: 10.1128/AAC.02416-20
      16
      In vivo targeting of Escherichia coli with vancomycin-arginine
      Neville, Lewis f.; Shalit, Itamar; Warn, Peter a.; Scheetz, Marc h.; Sun, Jiuzhi; Chosy, Madeline b.; Wender, Paul a.; Cegelski, Lynette; Rendell, Jacob t.
      Antimicrobial Agents and Chemotherapy (2021), 65 (4), e02416CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to Gram-neg. bacteria was investigated. Its MIC towards Escherichia coli, including β-lactamase expressing Ambler classes A, B, and D, was 8 to 16 μg/mL. Addn. of 8 times the MIC of V-r to E. coli was acutely bactericidal and assocd. with a low frequency of resistance (<2.32 x 10-10). In vivo, V-r markedly reduced E. coli burden by >7 log10 CFU/g in a thigh muscle model. These data warrant further development of V-r in combating E. coli, including resistant forms.
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    17. 17
      Antonoplis, A., Zang, X., Wegner, T., Wender, P. A., and Cegelski, L. (2019) Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant E. Coli and Targets Cell-Wall Synthesis. ACS Chem. Biol. 14 (9), 2065– 2070,  DOI: 10.1021/acschembio.9b00565
      17
      Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant E. coli and Targets Cell-Wall Synthesis
      Antonoplis, Alexandra; Zang, Xiaoyu; Wegner, Tristan; Wender, Paul A.; Cegelski, Lynette
      ACS Chemical Biology (2019), 14 (9), 2065-2070CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      The emergence of multi-drug-resistant Gram-neg. bacteria, including carbapenem-resistant Enterobacteriaceae, is a major health problem that necessitates the development of new antibiotics. Vancomycin inhibits cell-wall synthesis in Gram-pos. bacteria but is generally ineffective against Gram-neg. bacteria and is unable to penetrate the outer membrane barrier. To det. whether vancomycin and other antibiotics effective against Gram-pos. bacteria could, through modification, be rendered effective against Gram-neg. bacteria, we discovered that the covalent attachment of a single arginine to vancomycin yielded conjugates with order-of-magnitude improvements in activity against Gram-neg. bacteria, including pathogenic E. coli. The vancomycin-arginine conjugate (V-R) exhibited efficacy against actively growing bacteria, induced the loss of rod cellular morphol., and resulted in the intracellular accumulation of peptidoglycan precursors, all consistent with cell-wall synthesis disruption as its mechanism of action. Membrane permeabilization studies demonstrated an enhanced outer membrane permeability of V-R as compared with vancomycin. The conjugate exhibited no mammalian cell toxicity or hemolytic activity in MTT and hemolysis assays. Our study introduces a new vancomycin deriv. effective against Gram-neg. bacteria and underscores the broader potential of generating new antibiotics through combined mode-of-action and synthesis-informed design studies.
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    18. 18
      Vaara, M. (1992) Agents That Increase the Permeability of the Outer Membrane. Microbiol. Rev. 56 (3), 395– 411,  DOI: 10.1128/mr.56.3.395-411.1992
      18
      Agents that increase the permeability of the outer membrane
      Vaara, Martti
      Microbiological Reviews (1992), 56 (3), 395-411CODEN: MBRED3; ISSN:0146-0749.
      A review with 241 refs. on cationic agents and chelators as outer membrane permeabilizers, the mol. mechanism of outer membrane permeability increase, and bacterial strains resistant to the permeabilizers.
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    19. 19
      Ofek, I., Cohen, S., Rahmani, R., Kabha, K., Tamarkin, D., Herzig, Y., and Rubinstein, E. (1994) Antibacterial Synergism of Polymyxin B Nonapeptide and Hydrophobic Antibiotics in Experimental Gram-Negative Infections in Mice. Antimicrob. Agents Chemother. 38 (2), 374– 377,  DOI: 10.1128/AAC.38.2.374
      19
      Antibacterial synergism of polymyxin B nonapeptide and hydrophobic antibiotics in experimental gram-negative infections in mice
      Ofek, Izhak; Cohen, Sofie; Rahmani, Rita; Kabha, Kisra; Tamarkin, Dove; Herzig, Yaacov; Rubinstein, Ethan
      Antimicrobial Agents and Chemotherapy (1994), 38 (2), 374-7CODEN: AMACCQ; ISSN:0066-4804.
      Polymyxin B nonapeptide, derived by cleavage of the fatty acyl diaminobutryic acid from polymyxin B, is considerably less toxic, less bactericidal activity, and retains its ability to render gram-neg. bacteria susceptible to several antibiotics by permeabilizing their outer membranes. The peptide rendered all 53 polymyxin-susceptible strains tested more susceptible to novobiocin, lowering the MIC of novobiocin 8-fold or more. The combination of polymyxin B nonapeptide with novobiocin or with erythromycin administered i.p. in multiple doses synergistically protected mice infected with gram-neg. bacteria. This combination may be clin. useful because of the apparent rarity of the acquisition of resistance.
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    20. 20
      Velkov, T., Thompson, P. E., Nation, R. L., and Li, J. (2010) Structure--Activity Relationships of Polymyxin Antibiotics. J. Med. Chem. 53 (5), 1898– 1916,  DOI: 10.1021/jm900999h
      20
      Structure-Activity Relationships of Polymyxin Antibiotics
      Velkov, Tony; Thompson, Philip E.; Nation, Roger L.; Li, Jian
      Journal of Medicinal Chemistry (2010), 53 (5), 1898-1916CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review discussing the mechanisms of antibacterial activity of polymyxins, the mechanisms of resistance to polymyxins, the polymyxin-LPS complex, the synthesis of polymyxins, the structure-activity relationships of polymyxins, the polymyxin pharmacophore, and toxicol. properties of polymyxins.
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    21. 21
      Chiharha, S., Ito, A., Yahata, M., Tobita, T., and Koyama, Y. (1974) Chemical Synthesis, Isolation and Characterization of α-N-Fattyacyl Colistin Nonapeptide with Special Reference to the Correlation between Antimicrobial Activity and Carbon Number of Fattyacyl Moiety. Agric. Biol. Chem. 38 (3), 521– 529,  DOI: 10.1080/00021369.1974.10861184
      There is no corresponding record for this reference.
    22. 22
      Keirstead, N. D., Wagoner, M. P., Bentley, P., Blais, M., Brown, C., Cheatham, L., Ciaccio, P., Dragan, Y., Ferguson, D., Fikes, J., Galvin, M., Gupta, A., Hale, M., Johnson, N., Luo, W., McGrath, F., Pietras, M., Price, S., Sathe, A. G., Sasaki, J. C., Snow, D., Walsky, R. L., and Kern, G. (2014) Early Prediction of Polymyxin-Induced Nephrotoxicity with next-Generation Urinary Kidney Injury Biomarkers. Toxicol. Sci. 137 (2), 278– 291,  DOI: 10.1093/toxsci/kft247
      22
      Early Prediction of Polymyxin-Induced Nephrotoxicity With Next-Generation Urinary Kidney Injury Biomarkers
      Keirstead, Natalie D.; Wagoner, Matthew P.; Bentley, Patricia; Blais, Marie; Brown, Crystal; Cheatham, Letitia; Ciaccio, Paul; Dragan, Yvonne; Ferguson, Douglas; Fikes, Jim; Galvin, Melanie; Gupta, Anshul; Hale, Michael; Johnson, Nakpangi; Luo, Wenli; McGrath, Frank; Pietras, Mark; Price, Sally; Sathe, Abhishek G.; Sasaki, Jennifer C.; Snow, Debra; Walsky, Robert L.; Kern, Gunther
      Toxicological Sciences (2014), 137 (2), 278-291CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
      Despite six decades of clin. experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of std. of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) deriv. with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathol. and biomarker anal. of PMBN, an important test of the hypothesis that fatty acid modifications and charge redns. in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathol. injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clin. stds. of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathol. evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.
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    23. 23
      Vaara, M. (1983) Polymyxin B Nonapeptide Complexes with Lipopolysaccharide. FEMS Microbiol. Lett. 18 (1–2), 117– 121,  DOI: 10.1111/j.1574-6968.1983.tb00461.x
      23
      Polymyxin B nonapeptide complexes with lipopolysaccharide
      Vaara, M.
      FEMS Microbiology Letters (1983), 18 (1-2), 117-21CODEN: FMLED7; ISSN:0378-1097.
      Polymyxin B nonapeptide (I) did not sensitize a polymyxin-resistant pmrA mutant strain of Salmonella typhimurium to the hydrophobic agents novobiocin and fusidic acid, in contrast to the parent strain, and I, like polymyxin, inhibited the biol. activities of isolated lipopolysaccharide (gelation of Limulus hemocyte lysate, consumption of complement). Apparently, I causes a disorganization of the outer membrane by binding to the acidic groups of the lipopolysaccharide, as does polymyxin.
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    24. 24
      Brandenburg, K., Moriyon, I., Arraiza, M. D., Lewark-Yvetot, G., Koch, M. H. J., and Seydel, U. (2002) Biophysical Investigations into the Interaction of Lipopolysaccharide with Polymyxins. Thermochim. Acta 382 (1), 189– 198,  DOI: 10.1016/S0040-6031(01)00731-6
      24
      Biophysical investigations into the interaction of lipopolysaccharide with polymyxins
      Brandenburg, K.; Moriyon, I.; Arraiza, M. D.; Lewark-Yvetot, G.; Koch, M. H. J.; Seydel, U.
      Thermochimica Acta (2002), 382 (1-2), 189-198CODEN: THACAS; ISSN:0040-6031. (Elsevier Science B.V.)
      It is reported on the interaction of bacterial lipopolysaccharide (LPS, endotoxin), having different sugar chain length covalently bound to its hydrophobic moiety lipid A, with the polycationic antibiotics polymyxin B (PMB) and PMB-nonapeptide (PMBN). The binding enthalpies and the lipid:peptide binding stoichiometries were detd. by isothermal titrn. calorimetry (ITC). For LPS with a long sugar chain (S: smooth form LPS from Yersinia enterocolitica), the titrn. curves exhibit a strong exo-therm which can be interpreted to result from the electrostatic interaction of the neg. charges of the LPS with the pos. charges of the peptides. In contrast, the titrn. curves of LPS with a short sugar chain (LPS Re from Escherichia coli) and of free lipid A yield complex patterns of endo- and exo-therms, which result from the superposition of electrostatic binding, fluidization of the acyl chains and a transition between different three-dimensional aggregate structures of the endo-toxins due to peptide binding. IR spectroscopy indicates that the fluidizing effect of the polymyxins is similar for both types of LPS and for lipid A. Small-angle X-ray diffraction reveals, however, that the Re-type LPS and lipid A are converted from a cubic into a multilamellar structure, whereas, the S-form LPS transforms from a unilamellar into a multilamellar structure with a small no. of lamellae. The presented data allow a better understanding of the interaction of peptides with endotoxin mols.
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    25. 25
      Domalaon, R., Idowu, T., Zhanel, G. G., and Schweizer, F. (2018) Antibiotic Hybrids: The Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?. Clin. Microbiol. Rev. 31 (2), e00077– 17,  DOI: 10.1128/CMR.00077-17
      25
      Antibiotic hybrids: the next generation of agents and adjuvants against gram-negative pathogens?
      Domalaon, Ronald; Idowu, Temilolu; Zhanel, George G.; Schweizer, Frank
      Clinical Microbiology Reviews (2018), 31 (2), e00077-17/1-e00077-17/45CODEN: CMIREX; ISSN:1098-6618. (American Society for Microbiology)
      The global incidence of drug-resistant Gram-neg. bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-neg. bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-neg. bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clin. evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-neg. bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-neg. pathogens and/or expand the usefulness of our current antibiotic arsenal.
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    26. 26
      Duwe, A. K., Rupar, C. A., Horsman, G. B., and Vas, S. I. (1986) In Vitro Cytotoxicity and Antibiotic Activity of Polymyxin B Nonapeptide. Antimicrob. Agents Chemother. 30 (2), 340– 341,  DOI: 10.1128/AAC.30.2.340
      26
      In vitro cytotoxicity and antibiotic activity of polymyxin B nonapeptide
      Duwe, Axel K.; Rupar, C. Anthony; Horsman, Greg B.; Vas, Stephen I.
      Antimicrobial Agents and Chemotherapy (1986), 30 (2), 340-1CODEN: AMACCQ; ISSN:0066-4804.
      Polymyxin B nonapeptide, prepd. by enzymic removal of the fatty acyl diaminobutyric acid side chain from polymyxin B, was ∼100-fold less toxic to K562 cells than polymyxin B. Min. inhibitory concns. of polymyxin B nonapeptide against a test panel of bacteria were 2-64-fold lower than those of polymyxin B.
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    27. 27
      Domalaon, R., Yang, X., Lyu, Y., Zhanel, G. G., and Schweizer, F. (2017) Polymyxin B(3)-Tobramycin Hybrids with Pseudomonas Aeruginosa-Selective Antibacterial Activity and Strong Potentiation of Rifampicin, Minocycline, and Vancomycin. ACS Infect. Dis. 3 (12), 941– 954,  DOI: 10.1021/acsinfecdis.7b00145
      27
      Polymyxin B3-Tobramycin Hybrids with Pseudomonas aeruginosa-Selective Antibacterial Activity and Strong Potentiation of Rifampicin, Minocycline, and Vancomycin
      Domalaon, Ronald; Yang, Xuan; Lyu, Yinfeng; Zhanel, George G.; Schweizer, Frank
      ACS Infectious Diseases (2017), 3 (12), 941-954CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      There is an urgent need to develop novel antibacterial agents able to eradicate drug-resistant Gram-neg. pathogens such as Pseudomonas aeruginosa. Antimicrobial hybrids have emerged as a promising strategy to combat bacterial resistance, as a stand-alone drug but also as an adjuvant in combination with existing antibiotics. Herein, we report for the first time the synthesis and biol. evaluation of polymyxin-aminoglycoside heterodimers composed of polymyxin B3 covalently linked to tobramycin via an aliph. hydrocarbon linker. The polymyxin B3-tobramycin hybrids demonstrate potent activity against carbapenem-resistant as well as multidrug- or extensively drug-resistant (MDR/XDR) P. aeruginosa clin. isolates. Furthermore, the most potent hybrid was synergistic with currently used antibiotics against wild-type and MDR/XDR P. aeruginosa but also against Acinetobacter baumannii as well. The promising biol. activity described herein warrants addnl. studies into design and development of new antimicrobial hybrids able to surmount the problem of antimicrobial resistance.
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    28. 28
      Luther, A., Urfer, M., Zahn, M., Müller, M., Wang, S.-Y., Mondal, M., Vitale, A., Hartmann, J.-B., Sharpe, T., Monte, F. Lo, Kocherla, H., Cline, E., Pessi, G., Rath, P., Modaresi, S. M., Chiquet, P., Stiegeler, S., Verbree, C., Remus, T., Schmitt, M., Kolopp, C., Westwood, M.-A., Desjonquères, N., Brabet, E., Hell, S., LePoupon, K., Vermeulen, A., Jaisson, R., Rithié, V., Upert, G., Lederer, A., Zbinden, P., Wach, A., Moehle, K., Zerbe, K., Locher, H. H., Bernardini, F., Dale, G. E., Eberl, L., Wollscheid, B., Hiller, S., Robinson, J. A., and Obrecht, D. (2019) Chimeric Peptidomimetic Antibiotics against Gram-Negative Bacteria. Nature 576 (7787), 452– 458,  DOI: 10.1038/s41586-019-1665-6
      28
      Chimeric peptidomimetic antibiotics against Gram-negative bacteria
      Luther, Anatol; Urfer, Matthias; Zahn, Michael; Muller, Maik; Wang, Shuang-Yan; Mondal, Milon; Vitale, Alessandra; Hartmann, Jean-Baptiste; Sharpe, Timothy; Monte, Fabio Lo; Kocherla, Harsha; Cline, Elizabeth; Pessi, Gabriella; Rath, Parthasarathi; Modaresi, Seyed Majed; Chiquet, Petra; Stiegeler, Sarah; Verbree, Carolin; Remus, Tobias; Schmitt, Michel; Kolopp, Caroline; Westwood, Marie-Anne; Desjonqueres, Nicolas; Brabet, Emile; Hell, Sophie; LePoupon, Karen; Vermeulen, Annie; Jaisson, Regis; Rithie, Virginie; Upert, Gregory; Lederer, Alexander; Zbinden, Peter; Wach, Achim; Moehle, Kerstin; Zerbe, Katja; Locher, Hans H.; Bernardini, Francesca; Dale, Glenn E.; Eberl, Leo; Wollscheid, Bernd; Hiller, Sebastian; Robinson, John A.; Obrecht, Daniel
      Nature (London, United Kingdom) (2019), 576 (7787), 452-458CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      There is an urgent need for new antibiotics against Gram-neg. pathogens that are resistant to carbapenem and 3rd-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. We describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-neg. bacteria. Extensively optimized derivs. show potent activity against multidrug-resistant pathogens, including all of the Gram-neg. members of the ESKAPE pathogens. These derivs. also show favorable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclin. toxicol. studies that, if successful, will allow progress into clin. studies that have the potential to address life-threatening infections by the Gram-neg. pathogens, and thus to resolve a considerable unmet medical need.
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    29. 29
      Guan, D., Chen, F., Qiu, Y., Jiang, B., Gong, L., Lan, L., and Huang, W. (2019) Sulfonium, an Underestimated Moiety for Structural Modification, Alters the Antibacterial Profile of Vancomycin Against Multidrug-Resistant Bacteria. Angew. Chem., Int. Ed. 58 (20), 6678– 6682,  DOI: 10.1002/anie.201902210
      29
      Sulfonium, an Underestimated Moiety for Structural Modification, Alters the Antibacterial Profile of Vancomycin Against Multidrug-Resistant Bacteria
      Guan, Dongliang; Chen, Feifei; Qiu, Yunguang; Jiang, Bofeng; Gong, Likun; Lan, Lefu; Huang, Wei
      Angewandte Chemie, International Edition (2019), 58 (20), 6678-6682CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      In the antibiotics arsenal, vancomycin is a last resort for the treatment of intractable infections. However, this situation is under threat because of the increasing appearance of vancomycin-resistant bacteria (VRB). Herein, we report a series of novel vancomycin derivs. carrying a sulfonium moiety. The sulfonium-vancomycin derivs. exhibited enhanced antibacterial activity against VRB both in vitro and in vivo. These derivs. also exhibited activity against some Gram-neg. bacteria. The sulfonium modification enhanced the interaction of vancomycin with the bacterial cell membrane and disrupts membrane integrity. Furthermore, the in vivo pharmacokinetic profile, stability, and toxicity of these derivs. demonstrated good druggability of the sulfonium-vancomycin analogs. This work provides a promising strategy for combating drug-resistant bacterial infection, and advances the knowledge on sulfonium derivs. for structural optimization and drug development.
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    30. 30
      Shi, W., Chen, F., Zou, X., Jiao, S., Wang, S., Hu, Y., Lan, L., Tang, F., and Huang, W. (2021) Design, Synthesis, and Antibacterial Evaluation of Vancomycin-LPS Binding Peptide Conjugates. Bioorg. Med. Chem. Lett. 45, 128122,  DOI: 10.1016/j.bmcl.2021.128122
      30
      Design, synthesis, and antibacterial evaluation of vancomycin-LPS binding peptide conjugates
      Shi, Weiwei; Chen, Feifei; Zou, Xiangman; Jiao, Shang; Wang, Siqi; Hu, Yu; Lan, Lefu; Tang, Feng; Huang, Wei
      Bioorganic & Medicinal Chemistry Letters (2021), 45 (), 128122CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Developing novel antibiotics is urgently needed with emergency of drug resistance. Vancomycin, the last resort for intractable Gram-pos. bacterial infections, is ineffective against Gram-neg. bacteria and vancomycin resistant bacteria. Herein, we report a series of novel vancomycin derivs. carrying LPS binding peptides, vancomycin-LPS binding peptide conjugates (VPCs). The LPS binding peptides were conjugated onto 4 sites of vancomycin via CuAAC or maleimide- sulfydryl addn., and the formed VPCs were screened against VISA/VRE and Gram-neg. strains. VPCs exhibited enhanced activity against vancomycin resistant bacteria and obtained the activity against Gram-neg. bacteria in vitro, providing a novel strategy for vancomycin modification and glycopeptide antibiotics synthesis.
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    31. 31
      Yarlagadda, V., Akkapeddi, P., Manjunath, G. B., and Haldar, J. (2014) Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance. J. Med. Chem. 57 (11), 4558– 4568,  DOI: 10.1021/jm500270w
      31
      Membrane active vancomycin analogs: a strategy to combat bacterial resistance
      Yarlagadda, Venkateswarlu; Akkapeddi, Padma; Manjunath, Goutham B.; Haldar, Jayanta
      Journal of Medicinal Chemistry (2014), 57 (11), 4558-4568CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The alarming growth of antibiotic-resistant superbugs such as vancomycin-resistant enterococci and staphylococci has become a major global health hazard. To address this issue, the authors report the development of lipophilic cationic vancomycin analogs possessing excellent antibacterial activity against several drug-resistant strains. Compared to vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant Enterococci (VRE). Significantly, unlike vancomycin, these compds. were shown to be bactericidal at low concns. and did not induce bacterial resistance. An optimized compd. in the series, compared to vancomycin, showed higher activity in methicillin-resistant Staphylococcus aureus (MRSA) infected mouse model and exhibited superior antibacterial activity in whole blood with no obsd. toxicity. The remarkable activity of these compds. is attributed to the incorporation of a new membrane disruption mechanism into vancomycin and opens up a great opportunity for the development of novel antibiotics.
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    32. 32
      Okano, A., Isley, N. A., and Boger, D. L. (2017) Peripheral Modifications of [Ψ[CH2NH]Tpg4]Vancomycin with Added Synergistic Mechanisms of Action Provide Durable and Potent Antibiotics. Proc. Natl. Acad. Sci. U. S. A. 114, 5052– 5061,  DOI: 10.1073/pnas.1704125114
      32
      Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics
      Okano, Akinori; Isley, Nicholas A.; Boger, Dale L.
      Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (26), E5052-E5061CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Subsequent to binding pocket modifications designed to provide dual d-Ala-d-Ala/d-Ala-d-Lac binding that directly overcome the mol. basis of vancomycin resistance, peripheral structural changes have been explored to improve antimicrobial potency and provide addnl. synergistic mechanisms of action. A C-terminal peripheral modification, introducing a quaternary ammonium salt, is reported and was found to provide a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of d-Ala-d-Ala/d-Ala-d-Lac binding. This modification, which induces cell wall permeability and is complementary to the glycopeptide inhibition of cell wall synthesis, was found to provide improvements in antimicrobial potency (200-fold) against vancomycin-resistant Enterococci (VRE). Furthermore, it is shown that this type of C-terminal modification may be combined with a second peripheral (4-chlorobiphenyl)methyl (CBP) addn. to the vancomycin disaccharide to provide even more potent antimicrobial agents [VRE min. inhibitory concn. (MIC) = 0.01-0.005 μg/mL] with activity that can be attributed to three independent and synergistic mechanisms of action, only one of which requires d-Ala-d-Ala/d-Ala-d-Lac binding. Finally, it is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by VRE and that their durability against such challenges as well as their antimicrobial potency follow now predictable trends (three > two > one mechanisms of action). Such antibiotics are expected to display durable antimicrobial activity not prone to rapidly acquired clin. resistance.
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    33. 33
      Blaskovich, M. A. T., Hansford, K. A., Gong, Y., Butler, M. S., Muldoon, C., Huang, J. X., Ramu, S., Silva, A. B., Cheng, M., Kavanagh, A. M., Ziora, Z., Premraj, R., Lindahl, F., Bradford, T. A., Lee, J. C., Karoli, T., Pelingon, R., Edwards, D. J., Amado, M., Elliott, A. G., Phetsang, W., Daud, N. H., Deecke, J. E., Sidjabat, H. E., Ramaologa, S., Zuegg, J., Betley, J. R., Beevers, A. P. G., Smith, R. A. G., Roberts, J. A., Paterson, D. L., and Cooper, M. A. (2018) Protein-Inspired Antibiotics Active against Vancomycin- and Daptomycin-Resistant Bacteria. Nat. Commun. 9 (1), 1– 17,  DOI: 10.1038/s41467-017-02123-w
      33
      Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria
      Blaskovich, Mark A. T.; Hansford, Karl A.; Gong, Yujing; Butler, Mark S.; Muldoon, Craig; Huang, Johnny X.; Ramu, Soumya; Silva, Alberto B.; Cheng, Mu; Kavanagh, Angela M.; Ziora, Zyta; Premraj, Rajaratnam; Lindahl, Fredrik; Bradford, Tanya A.; Lee, June C.; Karoli, Tomislav; Pelingon, Ruby; Edwards, David J.; Amado, Maite; Elliott, Alysha G.; Phetsang, Wanida; Daud, Noor Huda; Deecke, Johan E.; Sidjabat, Hanna E.; Ramaologa, Sefetogi; Zuegg, Johannes; Betley, Jason R.; Beevers, Andrew P. G.; Smith, Richard A. G.; Roberts, Jason A.; Paterson, David L.; Cooper, Matthew A.
      Nature Communications (2018), 9 (1), 1-17CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biol. pathways via modulation of membrane-assocd. proteins and membrane lipid compn. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on pos. charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-pos. bacteria, and retain activity against glycopeptide-resistant strains. Optimized antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other i.v.-administered drugs that target membrane-assocd. receptors.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpsVWhtLs%253D&md5=ee332a92ea1fedfa78f83f3b3fe834be
    34. 34
      Wu, Z.-C., Cameron, M. D., and Boger, D. L. (2020) Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification. ACS Infect. Dis. 6 (8), 2169– 2180,  DOI: 10.1021/acsinfecdis.0c00258
      34
      Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification
      Wu, Zhi-Chen; Cameron, Michael D.; Boger, Dale L.
      ACS Infectious Diseases (2020), 6 (8), 2169-2180CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      A series of vancomycin C-terminus guanidine modifications is disclosed that improves antimicrobial activity, enhances the durability of antimicrobial action against selection or induction of resistance, and introduces a synergistic mechanism of action independent of D-Ala-D-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compds. examd. that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive but esp. vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of D-Ala-D-Ala/D-Lac binding and display superb antimicrobial potencies (MIC 0.6-0.15 μg/mL, VanA VRE). For the first time, we demonstrate that the synergistic behavior of the peripheral modifications examd. requires the presence of both the CBP and guanidine modifications in a single mol. vs. their combined use as an equimolar mixt. of singly modified compds. Finally, we show that a prototypical member of the series, G3-CBP-vancomycin (15), exhibits no hemolytic activity, displays no mammalian cell growth inhibition, possesses improved and esp. attractive in vivo pharmacokinetic (PK) properties, and displays excellent in vivo efficacy and potency against an esp. challenging multidrug-resistant (MRSA) and VanA vancomycin-resistant (VRSA) Staphylococcus aureus bacterial strain.
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    35. 35
      Sarkar, P., Basak, D., Mukherjee, R., Bandow, J. E., and Haldar, J. Alkyl-Aryl-Vancomycins: Multimodal Glycopeptides with Weak Dependence on the Bacterial Metabolic State. J. Med. Chem. 2021 64 (14), 10185− 10202 DOI: 10.1021/acs.jmedchem.1c00449
      35
      Alkyl-Aryl-Vancomycins: Multimodal Glycopeptides with Weak Dependence on the Bacterial Metabolic State
      Sarkar, Paramita; Basak, Debajyoti; Mukherjee, Riya; Bandow, Julia E.; Haldar, Jayanta
      Journal of Medicinal Chemistry (2021), 64 (14), 10185-10202CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Resistance to last-resort antibiotics such as vancomycin for Gram-pos. bacterial infections necessitates the development of new therapeutics. Furthermore, the ability of bacteria to survive antibiotic therapy through formation of biofilms and persister cells complicates treatment. Toward this, we report alkyl-aryl-vancomycins (AAVs), with high potency against vancomycin-resistant enterococci and staphylococci. Unlike vancomycin, the lead compd. AAV-qC10 was bactericidal and weakly dependent on bacterial metab. This resulted in complete eradication of non-growing cells of MRSA and disruption of its biofilms. In addn. to inhibiting cell wall biosynthesis like vancomycin, AAV-qC10 also depolarizes and permeabilizes the membrane. More importantly, the compd. delocalized the cell division protein MinD, thereby impairing bacterial growth through multiple pathways. The potential of AAV-qC10 is exemplified by its superior efficacy against MRSA in a murine thigh infection model as compared to vancomycin. This work paves the way for structural optimization and drug development for combating drug-resistant bacterial infections.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVygsrnL&md5=d7cc9f643c569d95486b76337de078fd
    36. 36
      Rostovtsev, V. V., Green, L. G., Fokin, V. V., and Sharpless, K. B. (2002) A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem., Int. Ed. 41 (14), 2596– 2599,  DOI: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4
      36
      A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes
      Rostovtsev, Vsevolod V.; Green, Luke G.; Fokin, Valery V.; Sharpless, K. Barry
      Angewandte Chemie, International Edition (2002), 41 (14), 2596-2599CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
      1,4-Disubstituted 1,2,3-triazoles I (R1 = PhCH2, PhCH2OCH2, 1-adamantyl, etc.; R2 = HO2C, Ph, PhOCH2, Et2NCH2, etc.) were readily and cleanly prepd. via highly efficient and regioselective copper(I)-catalyzed cycloaddn. of azides R1N3 with terminal alkynes R2C≡CH in 82-93% yields.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xls1Ohsr4%253D&md5=4603664be6639353b5e70f19b9f8d59f
    37. 37
      Tornøe, C. W., Christensen, C., and Meldal, M. (2002) Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 67 (9), 3057– 3064,  DOI: 10.1021/jo011148j
      37
      Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides
      Tornoe, Christian W.; Christensen, Caspar; Meldal, Morten
      Journal of Organic Chemistry (2002), 67 (9), 3057-3064CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      The cycloaddn. of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. This work reports a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddn. of terminal alkynes to azides on solid-phase. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddn. producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the x-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides were prepd. from Fmoc-amino alcs. by Mitsunobu reaction.
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    38. 38
      Silverman, S. M., Moses, J. E., and Sharpless, K. B. (2017) Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE. Chem. - Eur. J. 23 (1), 79– 83,  DOI: 10.1002/chem.201604765
      38
      Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE
      Silverman, Steven M.; Moses, John E.; Sharpless, K. Barry
      Chemistry - A European Journal (2017), 23 (1), 79-83CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Vancomycin has long been considered a drug of last resort. Its efficiency in treating multiple drug-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), has had a profound effect on the treatment of life-threatening infections. However, the emergence of resistance to vancomycin is a cause for significant worldwide concern, prompting the urgent development of new effective treatments for antibiotic resistant bacterial infections. Harnessing the benefits of multivalency and cooperativity against vancomycin-resistant strains, we report a Click Chem. approach towards reengineered vancomycin derivs. and the synthesis of a no. of dimers with increased potency against MRSA and vancomycin resistant Enterococci (VRE; VanB). These semi-synthetic dimeric ligands were linked together with great efficiency using the powerful CuAAC reaction, demonstrating high levels of selectivity and purity.
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    39. 39
      O’Dowd, H., Kim, B., Margolis, P., Wang, W., Wu, C., Lopez, S. L., and Blais, J. (2007) Preparation of Tetra-Boc-Protected Polymyxin B Nonapeptide. Tetrahedron Lett. 48 (11), 2003– 2005,  DOI: 10.1016/j.tetlet.2007.01.071
      39
      Preparation of tetra-Boc-protected polymyxin B nonapeptide
      O'Dowd, Hardwin; Kim, Bum; Margolis, Peter; Wang, Wen; Wu, Charlotte; Lopez, Sara L.; Blais, Johanne
      Tetrahedron Letters (2007), 48 (11), 2003-2005CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      A method for the selective tetra-Boc-protection of polymyxin B nonapeptide (PMBN) has been developed. Boc-ON selectively protects the amino side chains of the four diaminobutyric acid (Dab) residues in the presence of the N-terminal free amine.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhvVOrtrk%253D&md5=ce84a22fff3bb014682e102ada9a3de4
    40. 40
      Chevalier, S., Bouffartigues, E., Bodilis, J., Maillot, O., Lesouhaitier, O., Feuilloley, M. G. J., Orange, N., Dufour, A., and Cornelis, P. (2017) Structure, Function and Regulation of Pseudomonas Aeruginosa Porins. FEMS Microbiol. Rev. 41 (5), 698– 722,  DOI: 10.1093/femsre/fux020
      40
      Structure, function and regulation of Pseudomonas aeruginosa porins
      Chevalier, Sylvie; Bouffartigues, Emeline; Bodilis, Josselin; Maillot, Olivier; Lesouhaitier, Olivier; Feuilloley, Marc G. J.; Orange, Nicole; Dufour, Alain; Cornelis, Pierre
      FEMS Microbiology Reviews (2017), 41 (5), 698-722CODEN: FMREE4; ISSN:1574-6976. (Oxford University Press)
      A review. Pseudomonas aeruginosa is a Gram-neg. bacterium belonging to the γ -proteobacteria. Like other members of the Pseudomonas genus, it is known for its metabolic versatility and its ability to colonize a wide range of ecol. niches, such as rhizosphere, water environments and animal hosts, including humans where it can cause severe infections. Another particularity of P. aeruginosa is its high intrinsic resistance to antiseptics and antibiotics, which is partly due to its low outer membrane permeability. In contrast to Enterobacteria, pseudomonads do not possess general diffusion porins in their outer membrane, but rather express specific channel proteins for the uptake of different nutrients. The major outer membrane 'porin', OprF, has been extensively investigated, and displays structural, adhesion and signaling functions while its role in the diffusion of nutrients is still under discussion. Other porins include OprB and OprB2 for the diffusion of glucose, the two small outer membrane proteins OprG and OprH, and the two porins involved in phosphate/pyrophosphate uptake, OprP and OprO. The remaining nineteen porins belong to the so-called OprD (Occ) family, which is further split into two subfamilies termed OccD (8 members) and OccK (11 members). In the past years, a large amt. of information concerning the structure, function and regulation of these porins has been published, justifying why an updated review is timely.
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    41. 41
      Moore, R. A., Bates, N. C., and Hancock, R. E. (1986) Interaction of Polycationic Antibiotics with Pseudomonas Aeruginosa Lipopolysaccharide and Lipid A Studied by Using Dansyl-Polymyxin. Antimicrob. Agents Chemother. 29 (3), 496– 500,  DOI: 10.1128/AAC.29.3.496
      41
      Interaction of polycationic antibiotics with Pseudomonas aeruginosa lipopolysaccharide and lipid A studied by using dansyl-polymyxin
      Moore, Richard A.; Bates, Nancy C.; Hancock, Robert E. W.
      Antimicrobial Agents and Chemotherapy (1986), 29 (3), 496-500CODEN: AMACCQ; ISSN:0066-4804.
      A fluorescent deriv. of polymyxin B (dansyl-polymyxin) was used to study the interaction of polycations with lipopolysaccharide (LPS) and lipid A from P. aeruginosa. Dansyl-polymyxin became bound to LPS and lipid A sites, including Mg2+-binding sites, resulting in a 20-fold enhancement of fluorescence. A Hill plot of the binding data showed that the binding of dansyl-polymyxin to LPS was cooperative (n = 1.98) and of high affinity (S0.5 = 0.38 μM). The maximal binding capacity of LPS was ∼4 mol of dansyl-polymyxin/mol of LPS. The dansyl-polymyxin interaction with lipid A displayed similar kinetics (n = 2.26; S0.5 = 0.38 μM), and the maximal binding capacity was ∼2 mol of dansyl-polymyxin/mol lipid A. A variety of polycationic compds., including gentamicin, streptomycin, and polymyxin B, as well as Mg2+, were able to displace dansyl-polymyxin bound to LPS or to lipid A. Marked differences both in terms of the degree of displacement and in terms of the amt. of competing polycation required to displace a given amt. of dansyl-polymyxin were obsd. Addn. of excess polymyxin B resulted in displacement of all of the dansyl-polymyxin, demonstrating that only polymyxin-binding sites were being probed. Apparently, polymyxin B binds to multiple sites on LPS, including sites which bind aminoglycoside antibiotics and other polycationic compds.
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    42. 42
      Viljanen, P. and Vaara, M. (1984) Susceptibility of Gram-Negative Bacteria to Polymyxin B Nonapeptide. Antimicrob. Agents Chemother. 25 (6), 701– 705,  DOI: 10.1128/AAC.25.6.701
      42
      Susceptibility of gram-negative bacteria to polymyxin B nonapeptide
      Viljanen, P.; Vaara, M.
      Antimicrobial Agents and Chemotherapy (1984), 25 (6), 701-5CODEN: AMACCQ; ISSN:0066-4804.
      Subinhibitory concns. of polymyxin B nonapeptide sensitized all 21 polymyxin-susceptible gram-neg. bacterial strains studied to hydrophobic antibiotics such as fusidic acid, novobiocin, and erythromycin. The susceptibility increases were usually 30- and 300-fold. The strains included representatives of Escherichia coli with different O- and K-antigens, Klebsiella pneumoniae, K. oxytoca, Enterobacter cloacae, Enterobacter agglomerans, Salmonella typhimurium, Acinetobacter calcoaceticus, Pseudomonas aeruginosa, and P. maltophilia. In contrast, polymyxin-resistant strains (Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia stuartii, and Serratia marcescens) were resistant to the action of polyyxin B nonapeptide.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXks12ht7g%253D&md5=f612e1b3713f440e844845f548399319
    43. 43
      Healy, V. L., Lessard, I. A., Roper, D. I., Knox, J. R., and Walsh, C. T. (2000) Vancomycin Resistance in Enterococci: Reprogramming of the D-Ala-D-Ala Ligases in Bacterial Peptidoglycan Biosynthesis. Chem. Biol. 7, 109– 119,  DOI: 10.1016/S1074-5521(00)00116-2
      43
      Vancomycin resistance in enterococci: reprogramming of the D-Ala-D-Ala ligases in bacterial peptidoglycan biosynthesis
      Healy, Vicki L.; Lessard, Ivan A. D.; Roper, David I.; Knox, James R.; Walsh, Christopher T.
      Chemistry & Biology (2000), 7 (5), R109-R119CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Science Ltd.)
      A review with 53 refs. Vancomycin binds to bacterial cell wall intermediates to achieve its antibiotic effect. Infections of vancomycin-resistant enterococci are, however, becoming an increasing problem; the bacteria are resistant because they synthesize different cell wall intermediates. The enzymes involved in cell wall biosynthesis, therefore, are potential targets for combating this resistance. Recent biochem. and crystallog. results are providing mechanistic and structural details about some of these targets.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjvFenu78%253D&md5=843f504cb857b523e57ebb0fea4a0036
    44. 44
      Arnusch, C. J., Bonvin, A. M. J. J., Verel, A. M., Jansen, W. T. M., Liskamp, R. M. J., de Kruijff, B., Pieters, R. J., and Breukink, E. (2008) The Vancomycin–Nisin(1–12) Hybrid Restores Activity against Vancomycin Resistant Enterococci. Biochemistry 47 (48), 12661– 12663,  DOI: 10.1021/bi801597b
      44
      The vancomycin-nisin(1-12) hybrid restores activity against vancomycin resistant enterococci
      Arnusch, Christopher J.; Bonvin, Alexandre M. J. J.; Verel, Anne Marie; Jansen, Wouter T. M.; Liskamp, Rob M. J.; de Kruijff, Ben; Pieters, Roland J.; Breukink, Eefjan
      Biochemistry (2008), 47 (48), 12661-12663CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      Lipid II is a crucial component in bacterial cell wall synthesis. It is the target of a no. of important antibiotics, which include vancomycin and nisin. Here we show that a hybrid antibiotic that consists of vancomycin and nisin fragments is significantly more active than the sep. fragments against vancomycin-resistant enterococci. Three different hybrids were synthesized using click chem. and compared. Optimal spacer lengths and connection points were predicted using computer modeling.
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    45. 45
      van Hal, S. J., Paterson, D. L., and Lodise, T. P. (2013) Systematic Review and Meta-Analysis of Vancomycin-Induced Nephrotoxicity Associated with Dosing Schedules That Maintain Troughs between 15 and 20 mg per Liter. Antimicrob. Agents Chemother. 57 (2), 734– 744,  DOI: 10.1128/AAC.01568-12
      45
      Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter
      van Hal, S. J.; Paterson, D. L.; Lodise, T. P.
      Antimicrobial Agents and Chemotherapy (2013), 57 (2), 734-744CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/L. The widespread use of these more-intensive regimens has been assocd. with an increase in vancomycin-induced nephrotoxicity reports. The purpose of this systematic literature review is to det. the nephrotoxicity potential of maintaining higher troughs in clin. practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and Apr. 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥15 mg/L) were assocd. with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of <15 mg/L. The relationship between a trough of ≥15 mg/L and nephrotoxicity persisted when the anal. was restricted to studies that examd. only initial trough concns. (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥15 mg/L and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also obsd. with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concn. and duration of therapy.
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    46. 46
      Azad, M. A. K., Roberts, K. D., Yu, H. H., Liu, B., Schofield, A. V., James, S. A., Howard, D. L., Nation, R. L., Rogers, K., de Jonge, M. D., Thompson, P. E., Fu, J., Velkov, T., and Li, J. (2015) Significant Accumulation of Polymyxin in Single Renal Tubular Cells: A Medicinal Chemistry and Triple Correlative Microscopy Approach. Anal. Chem. 87 (3), 1590– 1595,  DOI: 10.1021/ac504516k
      46
      Significant Accumulation of Polymyxin in Single Renal Tubular Cells: A Medicinal Chemistry and Triple Correlative Microscopy Approach
      Azad, Mohammad A. K.; Roberts, Kade D.; Yu, Heidi H.; Liu, Boyin; Schofield, Alice V.; James, Simon A.; Howard, Daryl L.; Nation, Roger L.; Rogers, Kelly; de Jonge, Martin D.; Thompson, Philip E.; Fu, Jing; Velkov, Tony; Li, Jian
      Analytical Chemistry (Washington, DC, United States) (2015), 87 (3), 1590-1595CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Polymyxin is the last-line therapy against Gram-neg. 'superbugs'; however, dose-limiting nephrotoxicity can occur in up to 60% of patients after i.v. administration. Understanding the accumulation and concn. of polymyxin within renal tubular cells is essential for the development of novel strategies to ameliorate its nephrotoxicity and to develop safer, new polymyxins. We designed and synthesized a novel dual-modality iodine-labeled fluorescent probe for quant. mapping of polymyxin in kidney proximal tubular cells. Measured by synchrotron X-ray fluorescence microscopy, polymyxin concns. in single rat (NRK-52E) and human (HK-2) kidney tubular cells were approx. 1930- to 4760-fold higher than extracellular concns. Our study is the first to quant. measure the significant uptake of polymyxin in renal tubular cells and provides crucial information for the understanding of polymyxin-induced nephrotoxicity. Importantly, our approach represents a significant methodol. advancement in detn. of drug uptake for single-cell pharmacol.
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    47. 47
      Sakamoto, Y., Yano, T., Hanada, Y., Takeshita, A., Inagaki, F., Masuda, S., Matsunaga, N., Koyanagi, S., and Ohdo, S. (2017) Vancomycin Induces Reactive Oxygen Species-Dependent Apoptosis via Mitochondrial Cardiolipin Peroxidation in Renal Tubular Epithelial Cells. Eur. J. Pharmacol. 800, 48– 56,  DOI: 10.1016/j.ejphar.2017.02.025
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      Vancomycin induces reactive oxygen species-dependent apoptosis via mitochondrial cardiolipin peroxidation in renal tubular epithelial cells
      Sakamoto, Yuya; Yano, Takahisa; Hanada, Yuki; Takeshita, Aki; Inagaki, Fumika; Masuda, Satohiro; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro
      European Journal of Pharmacology (2017), 800 (), 48-56CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)
      Vancomycin (VCM) is a first-line antibiotic for serious infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is one of the most complaint in VCM therapy. We previously reported that VCM induced apoptosis in a porcine proximal tubular epithelial cell line (LLC-PK1), in which mitochondrial complex I may generate superoxide, leading to cell death. In the present study, VCM caused prodn. of mitochondrial reactive oxygen species and peroxidn. of the mitochondrial phospholipid cardiolipin that was reversed by administration of the mitochondrial uncoupler carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP). FCCP also significantly suppressed VCM-induced depolarization of the mitochondrial membrane and apoptosis. Moreover, the lipophilic antioxidant vitamin E and a mitochondria-targeted antioxidant, mitoTEMPO, also significantly suppressed VCM-induced depolarization of mitochondrial membrane and apoptosis, whereas vitamin C, n-acetyl cysteine, or glutathione did not provide significant protection. These findings suggest that peroxidn. of the mitochondrial membrane cardiolipin mediated the VCM-induced prodn. of intracellular reactive oxygen species and initiation of apoptosis in LLC-PK1 cells. Furthermore, regulation of mitochondrial function using a mitochondria-targeted antioxidant, such as mitoTEMPO, may constitute a potential strategy for mitigation of VCM-induced proximal tubular epithelial cell injury.
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    48. 48
      Jansen, J., Schophuizen, C. M. S., Wilmer, M. J., Lahham, S. H. M., Mutsaers, H. A. M., Wetzels, J. F. M., Bank, R. A., van den Heuvel, L. P., Hoenderop, J. G., and Masereeuw, R. (2014) A Morphological and Functional Comparison of Proximal Tubule Cell Lines Established from Human Urine and Kidney Tissue. Exp. Cell Res. 323 (1), 87– 99,  DOI: 10.1016/j.yexcr.2014.02.011
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      A morphological and functional comparison of proximal tubule cell lines established from human urine and kidney tissue
      Jansen, J.; Schophuizen, C. M. S.; Wilmer, M. J.; Lahham, S. H. M.; Mutsaers, H. A. M.; Wetzels, J. F. M.; Bank, R. A.; van den Heuvel, L. P.; Hoenderop, J. G.; Masereeuw, R.
      Experimental Cell Research (2014), 323 (1), 87-99CODEN: ECREAL; ISSN:0014-4827. (Elsevier B.V.)
      Promising renal replacement therapies include the development of a bioartificial kidney using functional human kidney cell models. In this study, human conditionally immortalized proximal tubular epithelial cell (ciPTEC) lines originating from kidney tissue (ciPTEC-T1 and ciPTEC-T2) were compared to ciPTEC previously isolated from urine (ciPTEC-U).Subclones of all ciPTEC isolates formed tight cell layers on Transwell inserts as detd. by transepithelial resistance, inulin diffusion, E-cadherin expression and immunocytochemisty. Extracellular matrix genes collagen I and -IV α1 were highly present in both kidney tissue derived matured cell lines (p<0.001) compared to matured ciPTEC-U, whereas matured ciPTEC-U showed a more pronounced fibronectin I and laminin 5 gene expression (p<0.01 and p<0.05, resp.). Expression of the influx carrier Org. Cation Transporter 2 (OCT-2), and the efflux pumps P-glycoprotein (P-gp), Multidrug Resistance Protein 4 (MRP4) and Breast Cancer Resistance Protein (BCRP) were confirmed in the three cell lines using real-time PCR and Western blotting. The activities of OCT-2 and P-gp were sensitive to specific inhibition in all models (p<0.001). The highest activity of MRP4 and BCRP was demonstrated in ciPTEC-U (p<0.05). Finally, active albumin reabsorption was highest in ciPTEC-T2 (p<0.001), while Na+-dependent phosphate reabsorption was most abundant in ciPTEC-U (p<0.01).In conclusion, ciPTEC established from human urine or kidney tissue display comparable functional PTEC specific transporters and physiol. characteristics, providing ideal human tools for bioartificial kidney development.
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    49. 49
      Nieskens, T. T. G., Peters, J. G. P., Schreurs, M. J., Smits, N., Woestenenk, R., Jansen, K., van der Made, T. K., Röring, M., Hilgendorf, C., Wilmer, M. J., and Masereeuw, R. (2016) A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity. AAPS J. 18 (2), 465– 475,  DOI: 10.1208/s12248-016-9871-8
      49
      A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity
      Nieskens, Tom T. G.; Peters, Janny G. P.; Schreurs, Marieke J.; Smits, Niels; Woestenenk, Rob; Jansen, Katja; van der Made, Thom K.; Roering, Melanie; Hilgendorf, Constanze; Wilmer, Martijn J.; Masereeuw, Rosalinde
      AAPS Journal (2016), 18 (2), 465-475CODEN: AJAOB6; ISSN:1550-7416. (Springer)
      Drug-induced nephrotoxicity still hampers drug development, because current translation from in vitro or animal studies to human lacks high predictivity. Often, renal adverse effects are recognized only during clin. stages of drug development. The current study aimed to establish a robust and a more complete human cell model suitable for screening of drug-related interactions and nephrotoxicity. In addn. to endogenously expressed renal org. cation transporters and efflux transporters, conditionally immortalized proximal tubule epithelial cells (ciPTEC) were completed by transduction of cells with the org. anion transporter (OAT) 1 or OAT3. Fluorescence-activated cell sorting upon exposure to the OAT substrate fluorescein successfully enriched transduced cells. A panel of org. anions was screened for drug-interactions in ciPTEC-OAT1 and ciPTEC-OAT3. The cytotoxic response to the drug-interactions with antivirals was further examd. by cell viability assays. Upon subcloning, concn.-dependent fluorescein uptake was found with a higher affinity for ciPTEC-OAT1 (Km = 0.8 ± 0.1 μM) than ciPTEC-OAT3 (Km = 3.7 ± 0.5 μM). Co-exposure to known OAT1 and/or OAT3 substrates (viz. para-aminohippurate, estrone sulfate, probenecid, furosemide, diclofenac, and cimetidine) in cultures spanning 29 passage nos. revealed relevant inhibitory potencies, confirming the robustness of our model for drug-drug interactions studies. Functional OAT1 was directly responsible for cytotoxicity of adefovir, cidofovir, and tenofovir, while a drug interaction with zidovudine was not assocd. with decreased cell viability. Our data demonstrate that human-derived ciPTEC-OAT1 and ciPTEC-OAT3 are promising platforms for highly predictive drug screening during early phases of drug development.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00318.

    • Synthetic schemes and synthesis of all building blocks; analytical RP-HPLC traces, HRMS analysis and yields for all new compounds synthesized; additional MIC analysis of building blocks and control compounds; MIC analysis in μM; hemolytic and PTEC toxicity data (PDF)


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