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 language | English |
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Pages (from-to) | 15878–15892 |
Number of pages | 15 |
Journal | Journal of Medicinal Chemistry |
Volume | 65 |
Issue number | 23 |
DOIs | |
Publication status | Published - 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