UB Paderborn / Katalog / Suche / Details

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

London: Nature Publishing Group UK

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 1 . 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. A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.

Sprache: Englisch
Identifikatoren: ISSN: 0028-0836
eISSN: 1476-4687
DOI: 10.1038/s41586-019-1665-6
Titel-ID: cdi_proquest_miscellaneous_2308518633

Format: –
Schlagworte: 101/58, 101/6, 631/326/22/1290, 639/638/309/555, 82, 82/16, 82/75, 82/80, 82/83, 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, Humanities and Social Sciences, 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, multidisciplinary, Multidrug resistance, Mutation, Natural products, Neutropenia, Pathogens, Peptides, Peptidomimetics - adverse effects, Peptidomimetics - chemistry, Peptidomimetics - pharmacology, Photoaffinity Labels, Physiological aspects, Prevention, Properties, Proteins, Science, Science (multidisciplinary), Toxicology

Weiterführende Literatur

Empfehlungen zum selben Thema automatisch vorgeschlagen von bX

Menü

Weitere Dienste

Einstellungen

Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Details

Weiterführende Literatur