Exploiting microbial regulatory networks to accelerate natural products discovery

PROJECT SUMMARY Microbes have been a fruitful source of bioactive natural products on a broad pharmaceutical spectrum. While traditional bioactivity-guided screening approaches have contributed to natural product discovery over the last decades, re-discovering known molecules, laborious protocols, and low compound concentrations have hindered substantial resource investment. The search for novel natural products has been revamped with technological advances metagenomics, pathway prediction tools, analytical techniques, and activation of silent biosynthetic genes using exogenous stimuli. However, non-optimal cultivation of organisms and uncontrolled expression of biosynthetic pathways in laboratory conditions currently conceal the full biosynthetic potential of microbial natural products. My laboratory works on developing genetic strategies for discovery and increased production of natural products. This research project will systematically characterize how regulatory networks control secondary metabolism, using genome-wide screens and multi-omics approaches to predict and access the unexplored biosynthetic potential of microbes. Uncovered molecular mechanisms will create an essential step towards the design of improved platform strains using first-principle models. Deciphering metabolic capabilities will provide a foundation for the large-scale production of novel, low abundant and unnatural analogues of natural products. Collectively, this research proposal has the transformative potential to accelerate the discovery, characterization, and commercialization of novel natural products as therapeutic leads.