CAREER: Leveraging polycyclic tetramate macrolactam biosynthesis as a model for understanding actinobacterial metabolic silencing

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Actinomycete bacteria produce a majority of our current antibiotics. Their genomes may harbor many more novel antibiotics. However, harnessing the full biosynthetic capacity of these microorganisms for drug and agrichemical discovery is challenging. This is because the majority of their biosynthetic gene clusters lack detectable products in the laboratory. This phenomenon, where predicted metabolic pathways fail to yield expected products, is termed biosynthetic silence. Representing one of the greatest biotechnological challenges to bioactive molecule discovery, biosynthetic silencing effectively hides much-needed new molecules from product development. This NSF CAREER project is designed to reveal the biological underpinnings of biosynthetic silence. Doing this will reveal new models of metabolic regulation that will be useful for activating silent genes and isolating their products for human gain. Importantly, this project demands a multidisciplinary approach and creates immersive scientific education opportunities at the high school, undergraduate and graduate school levels. Using polycyclic tetramate macrolactam (PTM) biosynthetic clusters as a model, this proposal probes the mechanisms responsible for biosynthetic cluster silencing in filamentous actinobacteria. PTM molecules have therapeutically interesting activities and their biosynthetic loci are well- conserved among these organisms. This commonality enables comparative metabologenomics across actinomycete families. Systematic assessment of PTM production within the Streptomyces griseus clade by the PI's group suggests silencing is determined by two interacting mechanisms: transcriptional regulation and metabolic control. Lessons learned from characterizing these mechanisms will be extended to actinobacteria outside of the S. griseus group towards understanding the evolution and induction of secondary metabolic regulation. Together, this work represents the first systematic application of comparative metabologenomics to reveal specific molecular-genetic and metabolic causes of biosynthetic silencing. Mechanistic understanding will likely reveal new strategies for therapeutic and agrichemical discovery via synthetic biology, fundamental for development of enhanced producing strains and more robust microbial functional genomic understanding.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.