Exploiting microbial regulatory networks to accelerate natural products discovery

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 lastdecades re-discovering known molecules laborious protocols and low compound concentrations have hindered substantial resource investment. The search for novel natural products has been revamped withtechnological advances metagenomics pathway prediction tools analytical techniques and activation ofsilent biosynthetic genes using exogenous stimuli. However non-optimal cultivation of organisms anduncontrolled expression of biosynthetic pathways in laboratory conditions currently conceal the fullbiosynthetic 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 characterizehow regulatory networks control secondary metabolism using genome-wide screens and multi-omicsapproaches to predict and access the unexplored biosynthetic potential of microbes. Uncovered molecularmechanisms will create an essential step towards the design of improved platform strains using first-principlemodels. Deciphering metabolic capabilities will provide a foundation for the large-scale production of novellow abundant and unnatural analogues of natural products. Collectively this research proposal has thetransformative potential to accelerate the discovery characterization and commercialization ofnovel natural products as therapeutic leads.