Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids

Cornelis J. Slingerland, Charlotte M. J. Wesseling, Paolo Innocenti, Koen G. C. Westphal, Rosalinde Masereeuw, Nathaniel I. Martin

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)15878–15892
Number of pages15
JournalJournal of Medicinal Chemistry
Volume65
Issue number23
DOIs
Publication statusPublished - 8 Dec 2022

Bibliographical note

Funding Information:
Funding was provided by the European Research Council (ERC consolidator grant to NIM, grant agreement no. 725523).

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

Keywords

  • Accumulation
  • Antibiotics
  • Antimicrobial activity
  • Colistin
  • Components
  • Derivatives
  • Gram-negative bacteria
  • Kidney injury
  • Nephrotoxicity
  • Nonapeptide

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