New approaches to target antibacterial agents toward
Gram-negative
bacteria are key, given the rise of antibiotic resistance. Since the
discovery of polymyxin B nonapeptide as a potent Gram-negative
outer membrane (OM)-permeabilizing synergist in the early 1980s, a
vast amount of literature on such synergists has been published. This
Review addresses a range of peptide-based and small organic compounds
that disrupt the OM to elicit a synergistic effect with antibiotics
that are otherwise inactive toward Gram-negative bacteria, with synergy
defined as a fractional inhibitory concentration index (FICI) of <0.5.
Another requirement for the inclusion of the synergists here covered
is their potentiation of a specific set of clinically used antibiotics:
erythromycin, rifampicin, novobiocin, or vancomycin. In addition,
we have focused on those synergists with reported activity against
Gram-negative members of the ESKAPE family of pathogens namely,
Escherichia coli
,
Pseudomonas aeruginosa
,
Klebsiella pneumoniae
, and/or
Acinetobacter
baumannii
. In cases where the FICI values were not directly
reported in the primary literature but could be calculated from the
published data, we have done so, allowing for more direct comparison
of potency with other synergists. We also address the hemolytic activity
of the various OM-disrupting synergists reported in the literature,
an effect that is often downplayed but is of key importance in assessing
the selectivity of such compounds for Gram-negative bacteria.
Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective...
Pentamidine, an FDA-approved
antiparasitic drug, was recently identified
as an outer membrane disrupting synergist that potentiates erythromycin,
rifampicin, and novobiocin against Gram-negative bacteria. The same
study also described a preliminary structure–activity relationship
using commercially available pentamidine analogues. We here report
the design, synthesis, and evaluation of a broader panel of bis-amidines
inspired by pentamidine. The present study both validates the previously
observed synergistic activity reported for pentamidine, while further
assessing the capacity for structurally similar bis-amidines to also
potentiate Gram-positive specific antibiotics against Gram-negative
pathogens. Among the bis-amidines prepared, a number of them were
found to exhibit synergistic activity greater than pentamidine. These
synergists were shown to effectively potentiate the activity of Gram-positive
specific antibiotics against multiple Gram-negative pathogens such
as
Acinetobacter baumannii
,
Klebsiella pneumoniae
,
Pseudomonas
aeruginosa,
and
Escherichia coli
, including polymyxin- and carbapenem-resistant strains.
With increasing rates of resistance toward commonly used antibiotics, especially among Gram-negative bacteria, there is renewed interested in polymyxins. Polymyxins are lipopeptide antibiotics with potent anti-Gram-negative activity and are generally believed to target lipid A, the lipopolysaccharide (LPS) anchor found in the outer membrane of Gram-negative bacteria. To characterize the stereochemical aspects of their mechanism(s) of action, we synthesized the full enantiomers of polymyxin B and the polymyxin B nonapeptide (PMBN). Both compounds were compared with the natural compounds in biological and biophysical assays, revealing strongly reduced antibacterial activity for the enantiomeric species. The enantiomeric compounds also exhibit reduced LPS binding, lower outer membrane (OM) permeabilization, and loss of synergetic potential. These findings provide new insights into the stereochemical requirements underlying the mechanisms of action of polymyxin B and PMBN.
Polymyxins are a class of lipopeptide anti-infective
agents with
potent and specific activity against Gram-negative bacteria. While
toxicity concerns associated with polymyxin B and E (colistin) have
historically limited their clinical application, today they are increasingly
used as last-resort antibiotics given the rise of multidrug-resistant
Gram-negative pathogens. The adverse side effects of polymyxins are
well known, particularly as related to their nephrotoxicity. Here,
we describe the synthesis and evaluation of a novel series of polymyxin
analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic
approach, we explored modifications of the exocyclic part of the polymyxin
scaffold, namely, the terminal amino acid and lipophilic tail. By
incorporating a reductively labile disulfide linkage in the lipid
tail, we obtained novel polymyxins that exhibit potent antibacterial
activity on par with polymyxin B but with reduced toxicity toward
human renal proximal tubular epithelial cells.
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