A novel antibiotic class targeting the lipopolysaccharide transporter.
Nature
; 625(7995): 566-571, 2024 Jan.
Article
en En
| MEDLINE
| ID: mdl-38172634
ABSTRACT
Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options1. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years1. 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 LptB2FGC 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 LptB2FGC as a tractable target for antimicrobial drug development.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana
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Lipopolisacáridos
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Antibacterianos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nature
/
Nature (Lond.)
/
Nature (London)
Año:
2024
Tipo del documento:
Article
País de afiliación:
Suiza