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A novel antibiotic class targeting the lipopolysaccharide transporter

Claudia Zampaloni, Patrizio Mattei, Konrad 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 Giorgio, Pauline Castel, David Dylus, Pawel Dzygiel, Antonio Felici, Fernando García-Alcalde, Andreas Haldimann, Matthew Leipner, Semen Leyn, Séverine Louvel, Pauline Misson, Andrei Osterman, Karanbir Pahil, Sébastien Rigo, Adrian Schäublin, Sebastian Scharf, Petra Schmitz, Theodor Stoll, Andrej Trauner, Sannah Zoffmann, Daniel Kahne, John A. T. Young, Michael A. Lobritz () and Kenneth A. Bradley ()
Additional contact information
Claudia Zampaloni: F. Hoffmann-La Roche
Patrizio Mattei: F. Hoffmann-La Roche
Konrad Bleicher: F. Hoffmann-La Roche
Lotte Winther: F. Hoffmann-La Roche
Claudia Thäte: F. Hoffmann-La Roche
Christian Bucher: F. Hoffmann-La Roche
Jean-Michel Adam: F. Hoffmann-La Roche
Alexander Alanine: F. Hoffmann-La Roche
Kurt E. Amrein: F. Hoffmann-La Roche
Vadim Baidin: Harvard University
Christoph Bieniossek: F. Hoffmann-La Roche
Caterina Bissantz: F. Hoffmann-La Roche
Franziska Boess: F. Hoffmann-La Roche
Carina Cantrill: F. Hoffmann-La Roche
Thomas Clairfeuille: F. Hoffmann-La Roche
Fabian Dey: F. Hoffmann-La Roche
Patrick Giorgio: F. Hoffmann-La Roche
Pauline Castel: F. Hoffmann-La Roche
David Dylus: F. Hoffmann-La Roche
Pawel Dzygiel: F. Hoffmann-La Roche
Antonio Felici: Discovery Microbiology, Aptuit (Verona) Srl, an Evotec Company
Fernando García-Alcalde: F. Hoffmann-La Roche
Andreas Haldimann: F. Hoffmann-La Roche
Matthew Leipner: F. Hoffmann-La Roche
Semen Leyn: Sanford Burnham Prebys Medical Discovery Institute
Séverine Louvel: F. Hoffmann-La Roche
Pauline Misson: F. Hoffmann-La Roche
Andrei Osterman: Sanford Burnham Prebys Medical Discovery Institute
Karanbir Pahil: Harvard University
Sébastien Rigo: F. Hoffmann-La Roche
Adrian Schäublin: F. Hoffmann-La Roche
Sebastian Scharf: F. Hoffmann-La Roche
Petra Schmitz: F. Hoffmann-La Roche
Theodor Stoll: F. Hoffmann-La Roche
Andrej Trauner: F. Hoffmann-La Roche
Sannah Zoffmann: F. Hoffmann-La Roche
Daniel Kahne: Harvard University
John A. T. Young: F. Hoffmann-La Roche
Michael A. Lobritz: F. Hoffmann-La Roche
Kenneth A. Bradley: F. Hoffmann-La Roche

Nature, 2024, vol. 625, issue 7995, 566-571

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-06873-0

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