Certain commensal Escherichia coli contain the clb biosynthetic gene cluster that codes for small molecule prodrugs known as precolibactins. Precolibactins are converted to colibactins by N-deacylation; the latter are postulated to be genotoxic and to contribute to colorectal cancer formation. E. coli use several self-immunity strategies to protect themselves against the activity of colibactin, among them the resistance protein ClbS. We have now determined that ClbS provides this protection by catalyzing hydrolysis of colibactin’s cyclopropane warhead. We have also reported the 2.1 Å X-ray structure of ClbS. The structure harbors a potential colibactin binding site and shares similarity to known hydrolases. ClbS also lacks the metal-binding motif found in other members of its superfamily, harboring instead a tyrosine residue in place of the metal ion. Computational docking of the ClbS substrate into the active site placed the cyclopropane moiety in proximity to this tyrosine residue, and its mutation to phenylalanine abolished the hydrolytic activity of ClbS, implicating tyrosine as a catalytic residue. As the cyclopropane has been shown to be essential for genotoxic effects in vitro, this ClbS-catalyzed ring-opening provides a means for the bacteria to circumvent self-induced genotoxicity. The identification of ClbS as a cyclopropane hydrolase provides insights into the resistance and toxicity mechanisms of colibactin and could be useful in developing treatment strategies.

Decoding the self-resistance mechanism of bacteria linked with colorectal cancer

256th National Meeting (2018)

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