作者
Claudia Zampaloni,Patrizio Mattei,Konrad H. Bleicher,Lotte Winther,Claudia Thäte,Christian Bucher,Jean‐Michel Adam,Alexander Alanine,Kurt E. Amrein,Vadim Baidin,Christoph Bieniossek,Caterina Bissantz,Franziska Boess,Carina Cantrill,Thomas Clairfeuille,Fabian Dey,Patrick Di Giorgio,Pauline du Castel,David Dylus,Paweł Dżygiel,Antonio Felici,Fernando García-Alcalde,Andreas Haldimann,Matthew Leipner,Semen A. Leyn,Séverine Louvel,Pauline Misson,Andrei L. Osterman,Karanbir S. Pahil,Sébastien Rigo,Adrian Schäublin,Sebastian Scharf,Petra Schmitz,Theodor Stoll,Andrej Trauner,Sannah Zoffmann,Daniel Kahne,John A. T. Young,Michael A. Lobritz,Kenneth A. Bradley
摘要
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.