Shining light on the dark matter of natural products

Structure and function of colibactin
mercredi, 27 novembre 2019 - 11:30 am
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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 likely to be 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 synergistic combination of chemical synthesis, genetics, and bioinformatics revealed the structure of colibactin, a bacterial metabolite lurking in this dark universe and 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. Our data suggests colibactin is better conceptualized as a reactive intermediate rather than a stable metabolic product. This work points to a general path to access the dark universe of natural products, and provides a foundation toward understanding microbiome-associated CRC.


Seth Herzon completed his undergraduate studies at Temple University, obtained a PhD from Harvard University in 2006 under the guidance of Andrew G. Myers, and was an NIH postdoctoral fellow with John F. Hartwig at the University of Illinois, Urbana–Champaign, from 2006–2008. He began his independent career at Yale in 2008, and is currently the Milton Harris ’29 Ph.D. Professor of Chemistry. He holds a joint appointment as Professor of Pharmacology at the Yale School of Medicine and is a member of the Yale Comprehensive Cancer Center. Herzon's research focuses on synthetic and translational studies of DNA damaging and microbiome-derived natural products, and antibiotic development.

Twitter: @HerzonLab