A novel antibiotic class targeting the lipopolysaccharide transporter
Author:
Zampaloni ClaudiaORCID, Mattei PatrizioORCID, Bleicher Konrad, Winther Lotte, Thäte Claudia, Bucher ChristianORCID, Adam Jean-Michel, Alanine AlexanderORCID, Amrein Kurt E., Baidin VadimORCID, Bieniossek Christoph, Bissantz Caterina, Boess FranziskaORCID, Cantrill CarinaORCID, Clairfeuille Thomas, Dey FabianORCID, Di Giorgio Patrick, du Castel Pauline, Dylus David, Dzygiel PawelORCID, Felici AntonioORCID, García-Alcalde FernandoORCID, Haldimann Andreas, Leipner MatthewORCID, Leyn SemenORCID, Louvel Séverine, Misson Pauline, Osterman AndreiORCID, Pahil KaranbirORCID, Rigo SébastienORCID, Schäublin Adrian, Scharf Sebastian, Schmitz Petra, Stoll Theodor, Trauner AndrejORCID, Zoffmann SannahORCID, Kahne DanielORCID, Young John A. T., Lobritz Michael A.ORCID, Bradley Kenneth A.ORCID
Abstract
AbstractCarbapenem-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.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference56 articles.
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