An 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, MA 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; Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands., Vermeulen BJA; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands., Harbig T; Integrative Transcriptomics, Center for Bioinformatics, University of Tübingen, 72070 Tübingen, Germany., Lavore F; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands., Kumar R; 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., Nieselt K; Integrative Transcriptomics, Center for Bioinformatics, University of Tübingen, 72070 Tübingen, Germany., Liu Y; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China., Bonvin AMJJ; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands., Baldus M; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands., Kubitscheck U; Clausius-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, MA 02138, USA., Nitti A; NovoBiotic Pharmaceuticals, Cambridge, MA 02138, USA., Schwalen CJ; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA., Spoering AL; NovoBiotic Pharmaceuticals, Cambridge, MA 02138, USA., Ling LL; NovoBiotic Pharmaceuticals, Cambridge, MA 02138, USA., Hughes D; NovoBiotic Pharmaceuticals, Cambridge, MA 02138, USA., Lelli M; Magnetic Resonance Center (CERM) and Department of Chemistry 'Ugo Schiff', University of Florence, via della Lastruccia 3, 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, MA 02115, USA., Schneider T; Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany. Electronic address: tschneider@uni-bonn.de., Weingarth M; NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands. Electronic address: m.h.weingarth@uu.nl.
Jazyk: angličtina
Zdroj: Cell [Cell] 2023 Sep 14; Vol. 186 (19), pp. 4059-4073.e27. Date of Electronic Publication: 2023 Aug 22.
DOI: 10.1016/j.cell.2023.07.038
Abstrakt: Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, 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, and lipid III 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 sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.
Competing Interests: Declaration of interests The following authors, A.J.P., C.A., A.N., A.L.S., L.L.L., D.H., and K.L., declare competing financial interests because they are employees and consultants of NovoBiotic Pharmaceuticals. A patent US 11,203,616 B2 was issued on 12/21/2021 and describes the use of clovibactin (Novo29) and as an antibiotic, as well as the pharmaceutical composition and antibiotic use of derivatives.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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