The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii

Jonathan M Tyrrell, Ali F Aboklaish, Timothy R Walsh, Timo Vaara, Martti Vaara

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The antibiotic crisis has reinstated polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective derivatives of polymyxins such as NAB739. Simultaneously, polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare. Here we show that NAB739 sensitizes the PMR strains to rifampin, a classic "anti-Gram-positive" antibiotic excluded by the intact outer membrane (OM) permeability barrier, as well as to retapamulin, the surrogate of lefamulin, an antibiotic under development against Gram-positive bacteria. Polymyxin B was used as a comparator. The combination of NAB739 and rifampin was synergistic against ten out of eleven PMR strains of Escherichia coli (Fractional Synergy Indices, FICs, 0.14-0.19) and that of NAB739 and retapamulin against all the tested eleven strains (FICs 0.19-0.25). Against PMR Klebsiella pneumoniae (n = 7), the FICs were 0.13-0.27 for NAB739 + rifampin and 0.14-0.28 for NAB739+retapamulin. Against Acinetobacter baumannii (n = 2), the combination of NAB739 and rifampin had the FIC of 0.09-0.19. Furthermore, NAB739 and meropenem were synergistic (FICs 0.25-0.50) against four out of five PMR strains that were simultaneously resistant to meropenem.

Original languageEnglish
Pages (from-to)149-153
Number of pages5
JournalPeptides
Volume112
DOIs
Publication statusPublished - Feb 2019

Bibliographical note

Copyright © 2018 Elsevier Inc. All rights reserved.

Keywords

  • Acinetobacter baumannii/drug effects
  • Anti-Bacterial Agents/pharmacology
  • Bacteria/drug effects
  • Drug Synergism
  • Escherichia coli/drug effects
  • Klebsiella pneumoniae/drug effects
  • Meropenem/pharmacology
  • Polymyxin B/pharmacology
  • Polymyxins/pharmacology
  • Rifampin/pharmacology

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