Invited
Shining light on the dark matter of natural products: Structure and function of colibactin.

The classical paradigm of large-scale production, isolation, and structural analysis has given us our understanding of almost all known natural products. Yet, advances in metabolomics, bioinformatics, and genetics suggest the existence of metastable, ultra-low abundance metabolites that pass undetected by the traditional isolation–analysis procedure. Analogous to the role of difficult-to-detect dark matter in shaping the universe in unanticipated ways, these dark metabolites may play significant roles in shaping human physiology and disease states. A new paradigm is required to find the structures and functions encoded here.

Here I’ll describe how a synergistic combination of chemical synthesis, genetics, and enzymology revealed the structure of colibactin, a dark bacterial metabolite implicated in gut microbiome-associated colorectal cancer (CRC). Colibactin’s presence was first detected in 2006, but because it is unstable and produced in vanishingly small quantities, its structure and mechanism of action could not be elucidated by classical approaches. We used techniques from a range of fields to infer the structure of colibactin and to construct a mechanistic model that explains its tumorigenic effects. This work provides a foundation to better understand gut microbiome-associated CRC and perhaps points to a general strategy to elucidate the structures and functions of dark natural products.