Show simple item record

dc.contributor.authorElliott, Alysha G
dc.contributor.authorHuang, Johnny X
dc.contributor.authorNeve, Søren
dc.contributor.authorZuegg, Johannes
dc.contributor.authorEdwards, Ingrid A
dc.contributor.authorCain, Amy K
dc.contributor.authorBoinett, Christine J
dc.contributor.authorBarquist, Lars
dc.contributor.authorLundberg, Carina Vingsbo
dc.contributor.authorSteen, Jason
dc.contributor.authorButler, Mark S
dc.contributor.authorMobli, Mehdi
dc.contributor.authorPorter, Kaela M
dc.contributor.authorBlaskovich, Mark A T
dc.contributor.authorLociuro, Sergio
dc.contributor.authorStrandh, Magnus
dc.contributor.authorCooper, Matthew A
dc.date.accessioned2022-06-16T13:11:09Z
dc.date.available2022-06-16T13:11:09Z
dc.date.issued2020-06-23
dc.date.submitted2020-02-12
dc.identifier.pmid32576824
dc.identifier.doi10.1038/s41467-020-16950-x
dc.identifier.urihttp://hdl.handle.net/10033/623233
dc.description.abstractPeptide 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 modelsen_US
dc.language.isoenen_US
dc.rightsAttribution-NonCommercial 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/*
dc.titleAn amphipathic peptide with antibiotic activity against multidrug-resistant Gram-negative bacteria.en_US
dc.typeArticleen_US
dc.identifier.eissn2041-1723
dc.identifier.journalNature communicationsen_US
dc.source.volume11
dc.source.issue1
dc.source.beginpage3184
dc.source.endpage
refterms.dateFOA2022-06-16T13:11:10Z
dc.source.journaltitleNature communications
dc.source.countryUnited Kingdom
dc.source.countryUnited Kingdom
dc.source.countryUnited Kingdom
dc.source.countryUnited Kingdom
dc.source.countryUnited Kingdom
dc.source.countryEngland


Files in this item

Thumbnail
Name:
ElliottNatComm2020.pdf
Size:
1.445Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial 4.0 International