A small molecule inhibitor prevents gut bacterial genotoxin production Journal Article
| Authors: | Volpe, M. R.; Velilla, J. A.; Daniel-Ivad, M.; Yao, J. J.; Stornetta, A.; Villalta, P. W.; Huang, H. C.; Bachovchin, D. A.; Balbo, S.; Gaudet, R.; Balskus, E. P. |
| Article Title: | A small molecule inhibitor prevents gut bacterial genotoxin production |
| 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. [Figure not available: see fulltext.] © 2022, The Author(s). |
| Keywords: | controlled study; unclassified drug; nonhuman; animal cell; mouse; phenotype; metabolism; enzyme inhibition; serine; animal experiment; enzyme inhibitor; drug design; biosynthesis; chemistry; drug mechanism; escherichia coli; catalysis; eukaryotic cell; intestine flora; enzyme binding; peptide hydrolases; deletion mutant; genotoxicity; peptide hydrolase; mutagens; peptidase; crystallography; covalent bond; biochemical analysis; bacterial toxin; polyketide; humans; human; article; mutagenic agent; gastrointestinal microbiome; colibactin; mrv 03 037; mrv 03 068; mrv 03 069; mrv 03 070; polyketides |
| Journal Title: | Nature Chemical Biology |
| Volume: | 19 |
| Issue: | 2 |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-02-01 |
| Start Page: | 159 |
| End Page: | 167 |
| Language: | English |
| DOI: | 10.1038/s41589-022-01147-8 |
| PUBMED: | 36253549 |
| PROVIDER: | scopus |
| PMCID: | PMC9889270 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2023 -- Source: Scopus |
