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 and Matthew A. Cooper ()
Additional contact information
Alysha G. Elliott: The University of Queensland
Johnny X. Huang: The University of Queensland
Søren Neve: Orphazyme
Johannes Zuegg: The University of Queensland
Ingrid A. Edwards: The University of Queensland
Amy K. Cain: Wellcome Sanger Institute
Christine J. Boinett: Wellcome Sanger Institute
Lars Barquist: Helmholtz Institute for RNA-based Infection Research (HIRI)
Carina Vingsbo Lundberg: Statens Serum Institut
Jason Steen: The University of Queensland
Mark S. Butler: The University of Queensland
Mehdi Mobli: The University of Queensland
Kaela M. Porter: Adenium Biotech ApS
Mark A. T. Blaskovich: The University of Queensland
Sergio Lociuro: BioVersys AG
Magnus Strandh: Adenium Biotech ApS
Matthew A. Cooper: The University of Queensland

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16950-x

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