A new antibiotic from an uncultured bacterium binds to an immutable target.

Autor: Shukla R; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.; Membrane Biochemistry and Biophysics, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands., Peoples AJ; NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA., Ludwig KC; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany., Maity S; Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands., Derks MGN; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.; Membrane Biochemistry and Biophysics, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands., de Benedetti S; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany., Krueger AM; Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany., Vermeulen BJA; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands., Lavore F; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands., Honorato RV; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands., Grein F; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany.; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany., Bonvin A; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands., Kubitscheck U; Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany., Breukink E; Membrane Biochemistry and Biophysics, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands., Achorn C; NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA., Nitti A; NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA., Schwalen CJ; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA., Spoering AL; NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA., Ling LL; NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA., Hughes D; NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA., Lelli M; Magnetic Resonance Center (CERM) and Department of Chemistry 'Ugo Schiff', University of Florence, via Sacconi 6, Sesto Fiorentino, 50019 Italy.; Consorzio Interuniversitario Risonanze Magnetiche MetalloProteine (CIRMMP), via Sacconi 6, Sesto Fiorentino, 50019 Italy., Roos WH; Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands., Lewis K; Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, Massachusetts 02115, USA., Schneider T; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany., Weingarth M; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 May 15. Date of Electronic Publication: 2023 May 15.
DOI: 10.1101/2023.05.15.540765
Abstrakt: Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, Lipid II, Lipid WTA ). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate, but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.
Databáze: MEDLINE