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Autor(en) / Beteiligte

Titel

A novel antibiotic class targeting the lipopolysaccharide transporter

Ist Teil von

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options . No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years . Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB FGC as a tractable target for antimicrobial drug development.

Sprache: Englisch
Identifikatoren: ISSN: 0028-0836, 1476-4687
eISSN: 1476-4687
DOI: 10.1038/s41586-023-06873-0
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10794144

Format: –
Schlagworte: Acinetobacter baumannii - drug effects, Acinetobacter baumannii - metabolism, Acinetobacter Infections - drug therapy, Acinetobacter Infections - microbiology, Animal models, Animals, Anti-Bacterial Agents - classification, Anti-Bacterial Agents - pharmacology, Antibacterial activity, Antibiotic resistance, Antibiotics, Antimicrobial agents, Bacteria, Bacterial infections, Biological Transport - drug effects, Carbapenems, Chemical activity, Disease Models, Animal, Drug Development, Drug dosages, Drug resistance, Drug Resistance, Multiple, Bacterial - drug effects, Gram-positive bacteria, High density lipoprotein, Humans, Hydrocarbons, Infections, Lipopolysaccharides, Lipopolysaccharides - metabolism, Lipoproteins, Membrane Transport Proteins - metabolism, Membranes, Mice, Microbial Sensitivity Tests, Mortality, Mutation, Optimization, Pathogens, Patients, Plasma, Standard of care

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