. 2023 Sep 14;186(19):4059-4073.e27.

doi: 10.1016/j.cell.2023.07.038. Epub 2023 Aug 22.

An antibiotic from an uncultured bacterium binds to an immutable target

Rhythm Shukla¹, Aaron J Peoples², Kevin C Ludwig³, Sourav Maity⁴, Maik G N Derks¹, Stefania De Benedetti³, Annika M Krueger⁴, Bram J A Vermeulen⁵, Theresa Harbig⁶, Francesca Lavore⁵, Raj Kumar⁵, Rodrigo V Honorato⁵, Fabian Grein⁷, Kay Nieselt⁶, Yangping Liu⁸, Alexandre M J J Bonvin⁵, Marc Baldus⁵, Ulrich Kubitscheck⁹, Eefjan Breukink¹⁰, Catherine Achorn², Anthony Nitti², Christopher J Schwalen¹¹, Amy L Spoering², Losee Lucy Ling², Dallas Hughes², Moreno Lelli¹², Wouter H Roos⁴, Kim Lewis¹³, Tanja Schneider¹⁴, Markus Weingarth¹⁵

Affiliations

¹ 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.
² NovoBiotic Pharmaceuticals, Cambridge, MA 02138, USA.
³ Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
⁴ Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands.
⁵ NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands.
⁶ Integrative Transcriptomics, Center for Bioinformatics, University of Tübingen, 72070 Tübingen, Germany.
⁷ Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
⁸ 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.
⁹ Clausius-Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany.
¹⁰ Membrane Biochemistry and Biophysics, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands.
¹¹ Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
¹² 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.
¹³ Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, MA 02115, USA.
¹⁴ 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.
¹⁵ NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands. Electronic address: m.h.weingarth@uu.nl.

PMID: 37611581
DOI: 10.1016/j.cell.2023.07.038

Free article

An antibiotic from an uncultured bacterium binds to an immutable target

Rhythm Shukla et al. Cell. 2023.

Free article

. 2023 Sep 14;186(19):4059-4073.e27.

doi: 10.1016/j.cell.2023.07.038. Epub 2023 Aug 22.

Authors

Affiliations

¹ 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.
² NovoBiotic Pharmaceuticals, Cambridge, MA 02138, USA.
³ Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany.
⁴ Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands.
⁵ NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands.
⁶ Integrative Transcriptomics, Center for Bioinformatics, University of Tübingen, 72070 Tübingen, Germany.
⁷ Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
⁸ 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.
⁹ Clausius-Institute for Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany.
¹⁰ Membrane Biochemistry and Biophysics, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands.
¹¹ Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
¹² 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.
¹³ Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, MA 02115, USA.
¹⁴ 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.
¹⁵ NMR Spectroscopy, Department of Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands. Electronic address: m.h.weingarth@uu.nl.

PMID: 37611581
DOI: 10.1016/j.cell.2023.07.038

Abstract

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 (C₅₅PP, 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.

Keywords: animal models; antibiotic resistance; antibiotics; atomic force microscopy; autolysis; cell wall; infection; lipid II; mechanism of action; peptidoglycan; solid-state NMR; uncultured bacteria.

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Conflict of interest statement

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.

Update of

A new antibiotic from an uncultured bacterium binds to an immutable target.
Shukla R, Peoples AJ, Ludwig KC, Maity S, Derks MGN, de Benedetti S, Krueger AM, Vermeulen BJA, Lavore F, Honorato RV, Grein F, Bonvin A, Kubitscheck U, Breukink E, Achorn C, Nitti A, Schwalen CJ, Spoering AL, Ling LL, Hughes D, Lelli M, Roos WH, Lewis K, Schneider T, Weingarth M. Shukla R, et al. bioRxiv [Preprint]. 2023 May 15:2023.05.15.540765. doi: 10.1101/2023.05.15.540765. bioRxiv. 2023. Update in: Cell. 2023 Sep 14;186(19):4059-4073.e27. doi: 10.1016/j.cell.2023.07.038. PMID: 37292624 Free PMC article. Updated. Preprint.

Comment in

Microbial 'dark matter' yields new antibiotic.
Kingwell K. Kingwell K. Nat Rev Drug Discov. 2023 Nov;22(11):872. doi: 10.1038/d41573-023-00156-z. Nat Rev Drug Discov. 2023. PMID: 37770758 No abstract available.

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An antibiotic from an uncultured bacterium binds to an immutable target

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An antibiotic from an uncultured bacterium binds to an immutable target

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Abstract

Conflict of interest statement

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