2. Academic Validation
  3. A new antibiotic from an uncultured bacterium binds to an immutable target

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

  • bioRxiv. 2023 May 15:2023.05.15.540765. doi: 10.1101/2023.05.15.540765.
Rhythm Shukla 1 2,  Aaron J Peoples 3,  Kevin C Ludwig 4,  Sourav Maity 5,  Maik G N Derks 1 2,  Stefania de Benedetti 4,  Annika M Krueger 6,  Bram J A Vermeulen 1,  Francesca Lavore 1,  Rodrigo V Honorato 1,  Fabian Grein 4 7,  Alexandre Bonvin 1,  Ulrich Kubitscheck 6,  Eefjan Breukink 2,  Catherine Achorn 3,  Anthony Nitti 3,  Christopher J Schwalen 8,  Amy L Spoering 3,  Losee Lucy Ling 3,  Dallas Hughes 3,  Moreno Lelli 9 10,  Wouter H Roos 5,  Kim Lewis 11,  Tanja Schneider 4,  Markus Weingarth 1
Affiliations

Affiliations

  • 1 NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
  • 2 Membrane Biochemistry and Biophysics, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
  • 3 NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA.
  • 4 Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 5 Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
  • 6 Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany.
  • 7 German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
  • 8 Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • 9 Magnetic Resonance Center (CERM) and Department of Chemistry "Ugo Schiff", University of Florence, via Sacconi 6, Sesto Fiorentino, 50019 Italy.
  • 10 Consorzio Interuniversitario Risonanze Magnetiche MetalloProteine (CIRMMP), via Sacconi 6, Sesto Fiorentino, 50019 Italy.
  • 11 Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, Massachusetts 02115, USA.
PMID: 37292624 DOI: 10.1101/2023.05.15.540765
Abstract

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.

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