2. Academic Validation
  3. A small molecule inhibitor prevents gut bacterial genotoxin production

A small molecule inhibitor prevents gut bacterial genotoxin production

  • Nat Chem Biol. 2022 Oct 17. doi: 10.1038/s41589-022-01147-8.
Matthew R Volpe 1,  José A Velilla 2,  Martin Daniel-Ivad 1,  Jenny J Yao 1,  Alessia Stornetta 3,  Peter W Villalta 3 4,  Hsin-Che Huang 5,  Daniel A Bachovchin 5,  Silvia Balbo 3 6,  Rachelle Gaudet 2,  Emily P Balskus 7 8
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 2 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
  • 3 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • 4 Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
  • 5 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
  • 7 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. balskus@chemistry.harvard.edu.
  • 8 Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. balskus@chemistry.harvard.edu.
PMID: 36253549 DOI: 10.1038/s41589-022-01147-8
Abstract

The human gut Bacterial genotoxin colibactin is a possible key driver of colorectal Cancer (CRC) development. Understanding colibactin's biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.

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