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

Autor:	Elliott AG; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD, 4072, Australia., Huang JX; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD, 4072, Australia.; School of Life Science and Technology, Weifang Medical University, Weifang, 261053, China., Neve S; Orphazyme, Ole Maaloesvej 3, 2200, Copenhagen, Denmark., Zuegg J; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD, 4072, Australia., Edwards IA; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD, 4072, Australia., Cain AK; Wellcome Sanger Institute, Hinxton, UK.; Department of Molecular Sciences, Macquarie University, NSW, 2109, Australia., Boinett CJ; Wellcome Sanger Institute, Hinxton, UK., Barquist L; Helmholtz Institute for RNA-based Infection Research (HIRI), Würzburg, Germany.; Faculty of Medicine, University of Würzburg, Würzburg, Germany., Lundberg CV; Statens Serum Institut, Copenhagen, Denmark., Steen J; School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, Qld, Australia., Butler MS; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD, 4072, Australia., Mobli M; Centre for Advanced Imaging, The University of Queensland, Queensland, Qld, Australia., Porter KM; Adenium Biotech ApS, Ole Maaloesvej 3, 2200, Copenhagen, Denmark., Blaskovich MAT; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD, 4072, Australia., Lociuro S; BioVersys AG, Hochbergerstrasse 60C, Technology Park, 4057, Basel, Switzerland., Strandh M; Adenium Biotech ApS, Ole Maaloesvej 3, 2200, Copenhagen, Denmark., Cooper MA; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD, 4072, Australia. m.cooper@uq.edu.au.; Trinity College Dublin, Dublin, Ireland. m.cooper@uq.edu.au.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Jun 23; Vol. 11 (1), pp. 3184. Date of Electronic Publication: 2020 Jun 23.
DOI:	10.1038/s41467-020-16950-x
Abstrakt:	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.
Databáze:	MEDLINE
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