An amphipathic peptide with antibiotic activity against multidrug-resistant Gram-negative bacteria
| Autor: | Mark E. Cooper, Alysha G. Elliott, Amy K. Cain, Ingrid A. Edwards, Mehdi Mobli, Carina Vingsbo Lundberg, Johnny X. Huang, Sergio Lociuro, Søren Neve, Magnus Strandh, Mark A. T. Blaskovich, Jason A. Steen, Kaela M. Porter, Mark S. Butler, Lars Barquist, Christine J. Boinett, Johannes Zuegg |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Carbapenem Cell Membrane Permeability Antibiotics General Physics and Astronomy Peptide Drug resistance Mice Drug Resistance Multiple Bacterial lcsh:Science chemistry.chemical_classification Multidisciplinary biology Drug discovery Helminth Proteins Haemolysis Anti-Bacterial Agents 3. Good health Urinary Tract Infections Female medicine.drug Membrane permeability medicine.drug_class Science 030106 microbiology Microbial Sensitivity Tests Peritonitis Article General Biochemistry Genetics and Molecular Biology Microbiology 03 medical and health sciences Gram-Negative Bacteria medicine Animals Humans Colistin Pneumonia General Chemistry Phospholipid transport biology.organism_classification Disease Models Animal 030104 developmental biology Carbapenems chemistry lcsh:Q Bacteria Antimicrobial Cationic Peptides |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020) Nature Communications Nature communications United Kingdom England |
| ISSN: | 2041-1723 |
| Popis: | 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. Peptide antibiotics often display a very narrow therapeutic index. Here, the authors present an optimized peptide antibiotic with broad-spectrum in vitro activities, in vivo efficacy in multiple disease models against multidrug-resistant Gram-negative infections, and reduced toxicity. |
| Databáze: | OpenAIRE |
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