Leveraging organic synthesis in microbiome-associated colorectal cancer: The synthetic journey to colibactin

Colibactin is a genotoxic metabolite produced by select bacteria in the human gut. The presence of colibactin producing bacteria has been correlated to human colorectal cancer progression and induces colorectal cancer in mouse models. Elucidating colibactin’s structure and mode of action is the key to deciphering the etiological role colibactin-producing bacteria play in colorectal cancer. Despite a world-wide effort, the structure of colibactin remained an unsolved problem for over a decade. Herein we describe the structural elucidation of colibactin with a focus on the critical contribution synthetic chemistry made within a broader interdisciplinary approach. Synthetic analysis of shunt metabolites and hypothesized intermediates produced by the bacteria provided key advances that ultimately led to elucidation of colibactin’s structure. These studies revealed that a commonly-used genetic modification, thought to promote formation of more stable biosynthetic products, actually derailed the biosynthetic pathway. Additionally, synthesis allowed for elucidation of the colibactin pharmacophore, and provided a molecular-level explanation for the well-known instability of the metabolite. Finally, chemical synthesis was used to unequivocally assign the structure of colibactin and reconcile the seemingly disparate structures of isolated metabolites. This overview highlights the dynamic role chemical synthetic studies can serve in multidisciplinary teams tackling complex problems at the interface of chemistry, biology, and human health.