Issue 11, 2023

Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity

Abstract

The growing incidence of infections caused by multi-drug resistant Gram-negative bacteria has led to an increased use of last-resort antibiotics such as the polymyxins. Polymyxin therapy is limited by toxicity concerns, most notably nephrotoxicity. Recently we reported the development of a novel class of semisynthetic polymyxins with reduced toxicity wherein the N-terminal lipid and diaminobutyric acid residue are replaced by a cysteine-linked lipid featuring a reductively labile disulfide bond. In the present study we further explored the potential of this approach by also varying the amino acid residue directly adjacent to the polymyxin macrocycle. This led to the identification of new semisynthetic polymyxins that maintain the potent antibacterial activity of the clinically used polymyxin B while exhibiting a further reduction in toxicity toward human proximal tubule epithelial cells. Furthermore, these new polymyxins were found to effectively synergize with novobiocin, rifampicin, and erythromycin against mcr-positive, polymyxin resistant E. coli.

Graphical abstract: Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity

Supplementary files

Article information

Article type
Research Article
Submitted
31 Aug 2023
Accepted
06 Oct 2023
First published
10 Oct 2023

RSC Med. Chem., 2023,14, 2417-2425

Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity

C. J. Slingerland, V. Lysenko, S. Chaudhuri, C. M. J. Wesseling, D. Barnes, R. Masereeuw and N. I. Martin, RSC Med. Chem., 2023, 14, 2417 DOI: 10.1039/D3MD00456B

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