Abstract
Gram-negative bacterial pathogens are intrinsically resistant to several antibiotics that are not able to penetrate the cell envelope barrier. The aim of this study was to identify peptides that at low concentrations induce susceptibility to these antibiotics in multidrug-resistant (MDR) Gram-negative bacterial strains of clinical relevance. Pairwise screening of 34 diverse peptides and four antibiotics (erythromycin, linezolid, rifampicin and vancomycin) with primary activity against Gram-positive bacteria identified 4 peptides that at submicromolar concentrations conferred susceptibility to rifampicin or erythromycin in Escherichia coli ATCC 25922. The identified peptides exhibited synergy with azithromycin and potentiated clindamycin in MDR E. coli ST131 and Klebsiella pneumoniae ST258. The low cytotoxicity toward eukaryotic cells (IC50 > 50 µM) observed for two of these peptides (KLWKKWKKWLK-NH2 and GKWKKILGKLIR-NH2) prompted synthesis and evaluation of the corresponding all-d analogues (D1 and D2), which retained similar synergistic antibacterial profiles. Low concentrations of D1 and D2 in combination with azithromycin and rifampicin inhibited growth of most clinical E. coli, K. pneumoniae and Acinetobacter baumannii strains tested. These data demonstrate that combinatorial screening at low peptide concentrations constitutes an efficient approach to identify clinically relevant peptide-antibiotic combinations. In vivo pharmacokinetic/pharmacodynamic and toxicity studies are needed to further validate the use of the peptides identified in this study for repurposing azithromycin and rifampicin against Gram-negative pathogens.
Highlights
Our data demonstrate that combinatorial screening at low concentrations constitutes an efficient approach to identify clinically relevant peptide-antibiotic combinations
Bacteria were cultured on Luria-Bertani broth, cation-adjusted Mueller-Hinton agar (MHA) and broth (MHBII)
Since potentiation of antibiotics is a frequent characteristic of cationic peptides, screening at low peptide concentrations (1 or 0.5 μM) and at clinically relevant antibiotic concentrations [11] would identify the most potent antibiotic potentiators, expediting the discovery of peptides with potential clinical utility
Summary
As a consequence of the worldwide spread of multidrug-resistant (MDR) Gram-negative clones, theWorld Health Organization has ranked the development of new therapeutics to treat infections caused by Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa as a critical priority [1].Intrinsic antibiotic resistance considerably limits the therapeutic options against these pathogens, since several classes of the available antibiotics cannot effectively penetrate the envelope barrier [2].Combination therapy represents an attractive approach for treating MDR infections as it typically reduces the required dose of the individual components and limits the risk for emergence of resistance [4,5].Antimicrobial peptides that increase therapeutic potency and expand the spectrum of antibiotics to includeGram-negative pathogens have potential use in combination therapy [4,5,6]. As a consequence of the worldwide spread of multidrug-resistant (MDR) Gram-negative clones, the. Intrinsic antibiotic resistance considerably limits the therapeutic options against these pathogens, since several classes of the available antibiotics cannot effectively penetrate the envelope barrier [2]. Combination therapy represents an attractive approach for treating MDR infections as it typically reduces the required dose of the individual components and limits the risk for emergence of resistance [4,5]. Antimicrobial peptides that increase therapeutic potency and expand the spectrum of antibiotics to include. Gram-negative pathogens have potential use in combination therapy [4,5,6]. Many reports have demonstrated synergistic peptide-antibiotic interactions, the clinical potential of such findings have rarely been studied systematically.
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