A novel antibiotic class targeting the lipopolysaccharide transporter PMID: 38172634

ADC Targets in Oncology

2026-04-10

A novel antibiotic class targeting the lipopolysaccharide transporter

Nature. 2024 Jan;625(7995):566-571. doi: 10.1038/s41586-023-06873-0.

Claudia Zampaloni ^# ¹ , Patrizio Mattei ^# ² , Konrad Bleicher ^# ² ³ , Lotte Winther ⁴ , Claudia Thäte ⁴ ⁵ , Christian Bucher ² , Jean-Michel Adam ² ⁶ , Alexander Alanine ² ⁷ , Kurt E Amrein ¹ , Vadim Baidin ⁸ , Christoph Bieniossek ¹ , Caterina Bissantz ⁴ , Franziska Boess ⁴ , Carina Cantrill ⁴ , Thomas Clairfeuille ² , Fabian Dey ² , Patrick Di Giorgio ² , Pauline du Castel ² , David Dylus ¹ , Pawel Dzygiel ⁴ , Antonio Felici ⁹ , Fernando García-Alcalde ¹ , Andreas Haldimann ¹ , Matthew Leipner ¹ ⁴ , Semen Leyn ¹⁰ , Séverine Louvel ¹ , Pauline Misson ¹ , Andrei Osterman ¹⁰ , Karanbir Pahil ⁸ , Sébastien Rigo ¹ , Adrian Schäublin ² ³ , Sebastian Scharf ¹¹ , Petra Schmitz ² , Theodor Stoll ² , Andrej Trauner ¹ , Sannah Zoffmann ² ¹² , Daniel Kahne ⁸ , John A T Young ¹ , Michael A Lobritz ¹³ , Kenneth A Bradley ¹⁴

Affiliations

1. Roche Pharma Research and Early Development, Immunology, Infectious Disease and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
2. Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
3. SixPeaks Bio, Basel, Switzerland.
4. Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
5. Preclinical Sciences and Translational Safety, Janssen Pharmaceutica, Beerse, Belgium.
6. AutoChem R&D, Mettler-Toledo International, Greifensee, Switzerland.
7. Independent consultant, Cambridge, Great Britain.
8. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
9. Discovery Microbiology, Aptuit (Verona) Srl, an Evotec Company, Verona, Italy.
10. Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
11. Roche Pharma Research and Early Development, Informatics, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
12. Therapeutics Discovery, Janssen Pharmaceutica, Beerse, Belgium.
13. Roche Pharma Research and Early Development, Immunology, Infectious Disease and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland. [email protected].
14. Roche Pharma Research and Early Development, Immunology, Infectious Disease and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland. [email protected].
# Contributed equally.

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.