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Chimeric peptidomimetic antibiotics against Gram-negative bacteria
Nature (London), 2019-12, Vol.576 (7787), p.452-458
2019
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Details

Autor(en) / Beteiligte
Titel
Chimeric peptidomimetic antibiotics against Gram-negative bacteria
Ist Teil von
  • Nature (London), 2019-12, Vol.576 (7787), p.452-458
Ort / Verlag
England: Nature Publishing Group
Erscheinungsjahr
2019
Quelle
MEDLINE
Beschreibungen/Notizen
  • There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens . These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that-if successful-will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.
Sprache
Englisch
Identifikatoren
ISSN: 0028-0836
eISSN: 1476-4687
DOI: 10.1038/s41586-019-1665-6
Titel-ID: cdi_proquest_miscellaneous_2308518633
Format
–
Schlagworte
Animals, Anti-Bacterial Agents - adverse effects, Anti-Bacterial Agents - chemistry, Anti-Bacterial Agents - pharmacology, Antibacterial agents, Antibiotics, Antimicrobial agents, Bacteria, Bacterial Outer Membrane Proteins - chemistry, Bacterial Outer Membrane Proteins - genetics, Binding proteins, Biocompatibility, Biological Products - chemistry, Cephalosporins, Colistin, Derivatives, Drug Discovery, Drug resistance, Drug resistance in microorganisms, Drug Resistance, Microbial - drug effects, Drug therapy, E coli, Escherichia coli Proteins - chemistry, Escherichia coli Proteins - genetics, Fluorescence, Folding, Gram-negative bacteria, Gram-Negative Bacteria - drug effects, Gram-Negative Bacteria - genetics, Gram-Negative Bacteria - pathogenicity, Gram-negative bacterial infections, Gram-positive bacteria, Health aspects, Humans, In vivo methods and tests, Infections, Lipids, Lipopolysaccharides, Lipopolysaccharides - chemistry, Macrocycles, Macrocyclic Compounds - adverse effects, Macrocyclic Compounds - chemistry, Macrocyclic Compounds - pharmacology, Male, Methods, Mice, Microbial Sensitivity Tests, Microbial Viability - drug effects, Microscopy, Electron, Transmission, Models, Molecular, Multidrug resistance, Mutation, Natural products, Neutropenia, Pathogens, Peptides, Peptidomimetics - adverse effects, Peptidomimetics - chemistry, Peptidomimetics - pharmacology, Photoaffinity Labels, Physiological aspects, Prevention, Properties, Proteins, Toxicology

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