New methods for activating silent biosynthetic gene clusters in bacteria

Microbial secondary metabolites represent a dominant source of pharmaceutical compounds and comprise some of our most celebrated cures.  While recent technological advances promise an unmatched understanding of secondary metabolism, a key challenge still remains.  The majority of biosynthetic gene clusters, the sets of genes responsible for the synthesis of secondary metabolites, are inactive when bacteria are cultured under standard laboratory conditions.  These so-called ‘silent’ gene clusters represent a large reservoir of potential therapeutics and methods that access this group of compounds would have a deep impact on drug discovery.  In this talk, I will present new approaches that my group has developed for activating silent biosynthetic pathways.  Application of these methods has unveiled small molecule elicitors and products of silent gene clusters.  In combination with profiling methodologies, these studies are beginning to provide a comprehensive picture of the structural basis of bacterial secondary metabolism as well as its chemogenetic modulation by exogenous small molecules.