article Open Access (hybrid) EN 2023-08-22

An antibiotic from an uncultured bacterium binds to an immutable target

Rhythm Shukla, Aaron J. Peoples, Kevin C. Ludwig, Sourav Maity, Maik G. N. Derks, Stefania De Benedetti, Annika M. Krueger, Bram J. A. Vermeulen, Theresa Harbig, Francesca Lavore, Raj Kumar, Rodrigo V. Honorato, Fabian Grein, Kay Nieselt, Yangping Liu, Alexandre M. J. J. Bonvin, Marc Baldus, Ulrich Kubitscheck, Eefjan Breukink, Catherine Achorn, Anthony Nitti, Christopher J. Schwalen, Amy L. Spoering, Losee L. Ling, Dallas E. Hughes, Moreno Lelli, Wouter H. Roos, Kim Lewis, Tanja Schneider, Markus Weingarth

Cell, Vol. 186, Issue 19, pp. 4059–4073.e27 (2023)

Utrecht University, NovoBiotic Pharmaceuticals, University of Bonn, University Hospital Bonn, University of Groningen, University of Tübingen, German Center for Infection Research, Tianjin Medical University, Novartis (United States), Interuniversity Consortium for Magnetic Resonance, University of Florence, Northeastern University

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

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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 (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.

Topics

Genomics and Phylogenetic Studies 1.00 Bacteriophages and microbial interactions 1.00 Bacterial Genetics and Biotechnology 0.99

Field: Biochemistry, Genetics and Molecular Biology · Subfield: Molecular Biology

Keywords

Lipid II,Biology,Bacterial cell structure,Peptidoglycan,Pyrophosphate,Bacteria,Antibiotics,Antibiotic resistance,Antimicrobial,Microbiology

MeSH Terms

Anti-Bacterial AgentsAnti-Bacterial AgentsAnti-Bacterial AgentsAnti-Bacterial AgentsAnti-Bacterial AgentsAnti-Bacterial AgentsAnti-Bacterial AgentsAnti-Bacterial Agents

UN Sustainable Development Goals

Good health and well-being (0.83)

All Available Versions

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Landing page — PubMed publishedVersion
Landing page — University of Groningen research database (University of Groningen / Centre for Information Technology) publishedVersion cc-by
Landing page — Utrecht University Repository (Utrecht University) submittedVersion other-oa
Landing page — Florence Research (University of Florence) submittedVersion other-oa

Citations by Year

2026	2025	2024	2023
29	59	47	8

APA

Rhythm Shukla, Aaron J. Peoples, Kevin C. Ludwig, Sourav Maity, Maik G. N. Derks, Stefania De Benedetti, Annika M. Krueger, Bram J. A. Vermeulen, Theresa Harbig, Francesca Lavore, Raj Kumar, Rodrigo V. Honorato, Fabian Grein, Kay Nieselt, Yangping Liu, Alexandre M. J. J. Bonvin, Marc Baldus, Ulrich Kubitscheck, Eefjan Breukink, Catherine Achorn, Anthony Nitti, Christopher J. Schwalen, Amy L. Spoering, Losee L. Ling, Dallas E. Hughes, Moreno Lelli, Wouter H. Roos, Kim Lewis, Tanja Schneider, Markus Weingarth (2023). An antibiotic from an uncultured bacterium binds to an immutable target. Cell, 186(19), 4059–4073.e27. https://doi.org/10.1016/j.cell.2023.07.038

MLA

Rhythm Shukla, et al. "An antibiotic from an uncultured bacterium binds to an immutable target." Cell, vol. 186, no. 19, 2023, pp. 4059–4073.e27. https://doi.org/10.1016/j.cell.2023.07.038

Chicago

Rhythm Shukla, Aaron J. Peoples, Kevin C. Ludwig, Sourav Maity, Maik G. N. Derks, Stefania De Benedetti, Annika M. Krueger, Bram J. A. Vermeulen, Theresa Harbig, Francesca Lavore, Raj Kumar, Rodrigo V. Honorato, Fabian Grein, Kay Nieselt, Yangping Liu, Alexandre M. J. J. Bonvin, Marc Baldus, Ulrich Kubitscheck, Eefjan Breukink, Catherine Achorn, Anthony Nitti, Christopher J. Schwalen, Amy L. Spoering, Losee L. Ling, Dallas E. Hughes, Moreno Lelli, Wouter H. Roos, Kim Lewis, Tanja Schneider, Markus Weingarth. "An antibiotic from an uncultured bacterium binds to an immutable target." Cell 186, no. 19 (2023): 4059–4073.e27. https://doi.org/10.1016/j.cell.2023.07.038

BibTeX

@article{shukla2023,
  title = { An antibiotic from an uncultured bacterium binds to an immutable target },
  author = { Rhythm Shukla and Aaron J. Peoples and Kevin C. Ludwig and Sourav Maity and Maik G. N. Derks and Stefania De Benedetti and Annika M. Krueger and Bram J. A. Vermeulen and Theresa Harbig and Francesca Lavore and Raj Kumar and Rodrigo V. Honorato and Fabian Grein and Kay Nieselt and Yangping Liu and Alexandre M. J. J. Bonvin and Marc Baldus and Ulrich Kubitscheck and Eefjan Breukink and Catherine Achorn and Anthony Nitti and Christopher J. Schwalen and Amy L. Spoering and Losee L. Ling and Dallas E. Hughes and Moreno Lelli and Wouter H. Roos and Kim Lewis and Tanja Schneider and Markus Weingarth },
  journal = { Cell },
  year = { 2023 },
  volume = { 186 },
  number = { 19 },
  pages = { 4059--4073.e27 },
  doi = { 10.1016/j.cell.2023.07.038 }
}

RIS

TY  - JOUR
TI  - An antibiotic from an uncultured bacterium binds to an immutable target
AU  - Rhythm Shukla
AU  - Aaron J. Peoples
AU  - Kevin C. Ludwig
AU  - Sourav Maity
AU  - Maik G. N. Derks
AU  - Stefania De Benedetti
AU  - Annika M. Krueger
AU  - Bram J. A. Vermeulen
AU  - Theresa Harbig
AU  - Francesca Lavore
AU  - Raj Kumar
AU  - Rodrigo V. Honorato
AU  - Fabian Grein
AU  - Kay Nieselt
AU  - Yangping Liu
AU  - Alexandre M. J. J. Bonvin
AU  - Marc Baldus
AU  - Ulrich Kubitscheck
AU  - Eefjan Breukink
AU  - Catherine Achorn
AU  - Anthony Nitti
AU  - Christopher J. Schwalen
AU  - Amy L. Spoering
AU  - Losee L. Ling
AU  - Dallas E. Hughes
AU  - Moreno Lelli
AU  - Wouter H. Roos
AU  - Kim Lewis
AU  - Tanja Schneider
AU  - Markus Weingarth
JO  - Cell
PY  - 2023
VL  - 186
IS  - 19
SP  - 4059
EP  - 4073.e27
DO  - 10.1016/j.cell.2023.07.038
ER  -

143

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