Photoactivated Colibactin Probes Induce Cellular DNA Damage.

Moodie LWK, Hubert M, Zhou X, Albers MF, Lundmark R, Wanrooij S, Hedberg C

Angew. Chem. Int. Ed. Engl. 58 (5) 1417-1421 [2019-01-28; online 2018-12-27]

Colibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks + bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative "warhead" and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks+ like phenotype in HeLa cells. Furthermore, results from DNA cross-linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.

Integrated Microscopy Technologies UmeƄ [Service]

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PubMed 30506956

DOI 10.1002/anie.201812326

Crossref 10.1002/anie.201812326