2024/01/03 by Claudia Zampaloni, Patrizio Mattei, Konrad Bleicher +37 · 1 voice · 5 citations
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #Antibiotic Resistance in Bacteria #Antimicrobial Peptides and Activities #Drug Transport and Resistance Mechanisms
paper · pdf · doi:10.1038/s41586-023-06873-0
openalex publication_date 2024/01/03 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
Abstract Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options 1 . No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years 1 . 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 2 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 2 FGC as a tractable target for antimicrobial drug development.