Organic Chemistry—Bristol Myers Squibb Symposium

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 point to the existence of a parallel natural products universe comprised of metastable, ultra-low abundance metabolites. This "dark" universe is far larger than the realm of known compounds, but the chemicals in this space are beyond the reach of classical isolation approaches. A new paradigm is required to find the structures and functions encoded here.

Here I'll describe how a novel synergistic combination of genetics, bioinformatics, and chemical synthesis revealed the structure of colibactin, a bacterial metabolite from this "dark universe" implicated in gut microbiome-associated colorectal cancer (CRC). Colibactin was discovered 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 utilized chemical synthesis to confirm the predicted structure and elucidate its reactivity. Our data suggests colibactin is better conceptualized as a reactive intermediate rather than a low-energy (stable) metabolic product. This work points to a general path to uncover the dark universe of natural products, and provides a foundation toward understanding microbiome-associated CRC.

Note: This is the second of two talks in the symposium. Bruce Ellsworth from Bristol Myers Squibb will give the first talk at 3:00 p.m.