An amphipathic peptide with antibiotic activity against multidrug-resistant Gram-negative bacteria

Alysha G. Elliott, Johnny X. Huang, Søren Neve, Johannes Zuegg, Ingrid A. Edwards, Amy K. Cain, Christine J. Boinett, Lars Barquist, Carina Vingsbo Lundberg, Jason Steen, Mark S. Butler, Mehdi Mobli, Kaela M. Porter, Mark A. T. Blaskovich, Sergio Lociuro, Magnus Strandh, Matthew A. Cooper*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Peptide antibiotics are an abundant and synthetically tractable source of molecular diversity, but they are often cationic and can be cytotoxic, nephrotoxic and/or ototoxic, which has limited their clinical development. Here we report structure-guided optimization of an amphipathic peptide, arenicin-3, originally isolated from the marine lugworm Arenicola marina. The peptide induces bacterial membrane permeability and ATP release, with serial passaging resulting in a mutation in mlaC, a phospholipid transport gene. Structure-based design led to AA139, an antibiotic with broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant bacteria, including ESBL, carbapenem- and colistin-resistant clinical isolates. The antibiotic induces a 3–4 log reduction in bacterial burden in mouse models of peritonitis, pneumonia and urinary tract infection. Cytotoxicity and haemolysis of the progenitor peptide is ameliorated with AA139, and the ‘no observable adverse effect level’ (NOAEL) dose in mice is ~10-fold greater than the dose generally required for efficacy in the infection models.

Original languageEnglish
Article number3184
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 23 Jun 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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