A small molecule inhibitor prevents gut bacterial genotoxin production

The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin’s biological effects remains difficult due to the instability of the proposed active species and the complexity of the gut microbiota. The authors report small-molecule boronic acid inhibitors of colibactin biosynthesis that mimic the precolibactin precursor and potently inhibit the colibactin-activating peptidase ClbP. Biochemical assays and crystallography show these compounds engage the ClbP binding pocket and form a covalent bond with the catalytic serine. The inhibitors reproduce phenotypes observed in a clbP deletion mutant and block colibactin’s genotoxic effects on eukaryotic cells. These ClbP inhibitors enable precise temporal control over colibactin production, facilitating studies of its role in CRC, and can be applied to related peptidase-encoding pathways to probe natural product biosynthesis.

Matthew R. Volpe, José A. Velilla, Martin Daniel-Ivad, Jenny J. Yao, Alessia Stornetta, Peter W. Villalta, Hsin-Che Huang, Daniel A. Bachovchin, Silvia Balbo, Rachelle Gaudet, Emily P. Balskus