10/17/19 - 9:45 AM to 11:00 AM
Department Seminar: Professor Douglas A. Mitchell
Big Data Genomics for Discovery of New Molecules and Enzyme Chemistry
The genomics revolution has thus far supplied us with more than 200,000 publicly available microbial genome sequences. Mining this vast resource for natural product biosynthetic gene clusters whose chemical products could hold future value to humankind is one avenue to fill the drug discovery pipeline. This process is relatively trivial for non-ribosomal peptide and polyketide natural products, owing to the large size of the requisite biosynthetic genes and the genetic commonality within each compound class. Considerably more challenging is the bioinformatic identification of ribosomally synthesized and post-translationally modified peptides, the so-called RiPP natural products, of which there are now over 30 distinct structural classes that often surpass NRPS and PKS products in their structural complexity, breadth of bioactivities, and phylogenetic distribution. RiPP biosynthetic pathways and the resulting natural products are a largely untapped source of new chemical matter created in ways that challenge existing biochemical paradigms.
This lecture will cover our motivations, initial forays, and ongoing work in how big data genomics, high-throughput mining, and reactivity-based screening can be brought to bear in cataloguing all observable members of a desired class of RiPP. Retrospective analysis of these specific datasets naturally leads to the generation of new biosynthetic and mechanistic hypotheses while also accelerating the discovery of new members of that RiPP class. By focusing on divergence within protein sequence-function space, one can even discover first-in-class RiPPs using bioinformatic approaches, which stands in contrast to popular belief. With the prevalence of RiPP biosynthesis starting to come into focus, early estimates suggest this molecular class will far outnumber other classes of specialized microbial metabolites.
Professor Mitchell's primary research objective is to use a blend of chemical and biological approaches to address the alarming rise in antibiotic resistance. In this endeavour, researchers in his group seek to identify and characterize novel antibiotic compounds. Their research involves the characterization of novel natural products and employs synthetic methods to reveal both biological mode of action and structure-activity relationships. Further, researchers evaluate the mechanistic details of key biosynthetic enzymes for the purposes of analog generation. Taken together, their work aims to expedite the discovery of future medicines from biological sources. Of special interest are compounds that only kill pathogenic bacteria or directly target mechanisms of virulence. Unlike currently deployed antibiotics, which exclusively target essential life processes, their strategy holds great potential in delaying resistance.
About Professor Mitchell
Professor Mitchell received his undergraduate degree in chemistry from Carnegie Mellon University. After a short internship in medicinal chemistry at Merck Research Laboratories, he obtained his doctorate from the University of California, Berkeley. For postdoctoral studies, he worked at the University of California, San Diego. He joined the University of Illinois faculty in 2009.