Photoactivated Colibactin Probes Induce Cellular DNA Damage

Abstract

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.

Design, Synthesis, and Biological Evaluation of Light-Activated Antibiotics

“…Photoactivation of caged compounds enables the spatiotemporal regulation of the activity of the drugs of interest, which has been successfully applied as powerful tools in biological studies. There are many examples of successful utilization of photocaging handles directly on antitumor drugs, [30][31][32][33] neurotransmitters, [34][35][36] or peptides. 37 Related to antibiotics, there have been many examples of photoswitchable groups attached to antibiotics, which have been demonstrated to successfully inhibit bacterial growth by irradiation.…”