Genetically encoded small molecules, also known as natural products, have inspired the majority of FDA approved anti-infective and anti-cancer agents.  Bacterial natural products have been particularly productive sources of therapeutically relevant small molecules.  One of the key insights to arise from the large-scale sequencing of bacterial genomic DNA is that traditional methods used to discover bacterial natural products have only provided access to a small fraction of the biosynthetic diversity encoded by prokaryotes.  These studies indicate that 1) the majority of bacteria present in nature have not been cultured in the laboratory and 2) for even easily cultured bacteria, only a small subset of the biosynthetic gene clusters present in their genomes is expressed under laboratory fermentation conditions.  We are using both functional and sequence-based strategies to access bioactive small molecules from these, until now, inaccessible sources.  New small molecule antibiotics, anticancer agents and virulence factors that we have uncovered in these studies, as well as the modes of action of these metabolites, will be described.

Genomic approaches for the discovery of new bioactive bacterial metabolites

244th National Meeting (2012)

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