A novel antibiotic class targeting the lipopolysaccharide transporter

• Published in: Nature (London) Vol. 625; no. 7995; pp. 566 - 571
• Main Authors: Zampaloni, Claudia, Mattei, Patrizio, Bleicher, Konrad, Winther, Lotte, Thäte, Claudia, Bucher, Christian, Adam, Jean-Michel, Alanine, Alexander, Amrein, Kurt E, Baidin, Vadim, Bieniossek, Christoph, Bissantz, Caterina, Boess, Franziska, Cantrill, Carina, Clairfeuille, Thomas, Dey, Fabian, Di Giorgio, Patrick, du Castel, Pauline, Dylus, David, Dzygiel, Pawel, Felici, Antonio, García-Alcalde, Fernando, Haldimann, Andreas, Leipner, Matthew, Leyn, Semen, Louvel, Séverine, Misson, Pauline, Osterman, Andrei, Pahil, Karanbir, Rigo, Sébastien, Schäublin, Adrian, Scharf, Sebastian, Schmitz, Petra, Stoll, Theodor, Trauner, Andrej, Zoffmann, Sannah, Kahne, Daniel, Young, John A T, Lobritz, Michael A, Bradley, Kenneth A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.01.2024; Nature Publishing Group UK
• Subjects: Acinetobacter baumannii - drug effects; Acinetobacter baumannii - metabolism; Acinetobacter Infections - drug therapy; Acinetobacter Infections - microbiology; Animal models; Animals; Anti-Bacterial Agents - classification; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antibiotic resistance; Antibiotics; Antimicrobial agents; Bacteria; Bacterial infections; Biological Transport - drug effects; Carbapenems; Chemical activity; Disease Models, Animal; Drug Development; Drug dosages; Drug resistance; Drug Resistance, Multiple, Bacterial - drug effects; Gram-positive bacteria; High density lipoprotein; Humans; Hydrocarbons; Infections; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lipoproteins; Membrane Transport Proteins - metabolism; Membranes; Mice; Microbial Sensitivity Tests; Mortality; Mutation; Optimization; Pathogens; Patients; Plasma; Standard of care
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06873-0

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options . No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years . 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 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 FGC as a tractable target for antimicrobial drug development.