An amphipathic peptide with antibiotic activity against multidrug-resistant Gram-negative bacteria.
Animals
Anti-Bacterial Agents
/ chemistry
Antimicrobial Cationic Peptides
/ chemistry
Carbapenems
/ pharmacology
Cell Membrane Permeability
/ drug effects
Colistin
/ pharmacology
Disease Models, Animal
Drug Discovery
Drug Resistance, Multiple, Bacterial
/ drug effects
Female
Gram-Negative Bacteria
/ drug effects
Helminth Proteins
/ chemistry
Humans
Male
Mice
Microbial Sensitivity Tests
Peritonitis
/ drug therapy
Pneumonia
/ drug therapy
Urinary Tract Infections
/ drug therapy
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 06 2020
23 06 2020
Historique:
received:
12
02
2020
accepted:
03
06
2020
entrez:
25
6
2020
pubmed:
25
6
2020
medline:
28
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32576824
doi: 10.1038/s41467-020-16950-x
pii: 10.1038/s41467-020-16950-x
pmc: PMC7311426
doi:
Substances chimiques
Anti-Bacterial Agents
0
Antimicrobial Cationic Peptides
0
Carbapenems
0
Helminth Proteins
0
Colistin
Z67X93HJG1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3184Subventions
Organisme : Medical Research Council
ID : G1100100
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT104797/Z/14/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT098051
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100100/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
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