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Repurposing Azithromycin and Rifampicin Against Gram-Negative Pathogens by Combination With Peptidomimetics

Authors
  • Baker, Kristin R.1, 2
  • Jana, Bimal1, 2
  • Hansen, Anna Mette3
  • Nielsen, Hanne Mørck4
  • Franzyk, Henrik3
  • Guardabassi, Luca1, 5
  • 1 Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg , (Denmark)
  • 2 Department of Biomedical Sciences, Ross University School of Veterinary Medicine, Basseterre , (St. Kitts & Nevis)
  • 3 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen , (Denmark)
  • 4 Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen , (Denmark)
  • 5 Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield , (United Kingdom)
Type
Published Article
Journal
Frontiers in Cellular and Infection Microbiology
Publisher
Frontiers Media SA
Publication Date
Jul 02, 2019
Volume
9
Identifiers
DOI: 10.3389/fcimb.2019.00236
PMID: 31334131
PMCID: PMC6615261
Source
PubMed Central
Keywords
License
Unknown

Abstract

Synthetic peptidomimetics may be designed to mimic functions of antimicrobial peptides, including potentiation of antibiotics, yet possessing improved pharmacological properties. Pairwise screening of 42 synthetic peptidomimetics combined with the antibiotics azithromycin and rifampicin in multidrug-resistant (MDR) Escherichia coli ST131 and Klebsiella pneumoniae ST258 led to identification of two subclasses of α-peptide/β-peptoid hybrids that display synergy with azithromycin and rifampicin (fractional inhibitory concentration indexes of 0.03–0.38). Further screening of the best three peptidomimetics in combination with a panel of 21 additional antibiotics led to identification of peptidomimetics that potentiated ticarcillin/clavulanate and erythromycin against E. coli , and clindamycin against K. pneumoniae . The study of six peptidomimetics was extended to Pseudomonas aeruginosa , confirming synergy with antibiotics for five of them. The most promising compound, H-(Lys-βNPhe)8-NH2, exerted only a minor effect on the viability of mammalian cells (EC50 ≥ 124–210 μM), and thus exhibited the highest selectivity toward bacteria. This compound also synergized with rifampicin and azithromycin at sub-micromolar concentrations (0.25–0.5 μM), thereby inducing susceptibility to these antibiotics at clinically relevant concentrations in clinical MDR isolates. This peptidomimetic lead and its analogs constitute promising candidates for efficient repurposing of rifampicin and azithromycin against Gram-negative pathogens.

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