TITLE:Uncovering the Dark Matter of Microbial Metabolomes
Microbial natural products serve as a dominant source of pharmaceutical agents and comprise some of our most celebrated cures. Recent discovery efforts, however, have been plagued by the frequent re-isolation of old molecules. One of the underlying reasons is that the vast majority of natural product biosynthetic genes in a given bacterium are expressed at low levels, when cultured under standard laboratory conditions. These so-called ‘silent’ or ‘cryptic’ gene clusters represent a large reservoir of bioactive molecules and methods that access them would have a profound impact on natural product research and thereby on drug discovery. In this talk, I will present new strategies that my group has developed for activating silent biosynthetic gene clusters. Application of these approaches to diverse bacteria has unveiled not only the products of silent clusters, but also small molecule elicitors, which in most cases are growth-inhibitory or antibiotic in nature. These insights have led to the idea that old antibiotics may be used to find new ones. The mechanisms underlying this phenomenon will be discussed as well as the ecological relevance of cryptic metabolites.