Metagenomic approaches for the discovery of new bioactive natural products

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) only a small subset of the biosynthetic gene clusters found in the genomes of cultured bacteria is expressed under laboratory fermentation conditions. We are using both functional and sequence-based strategies to access previously inaccessible bioactive small molecules from both environmental bacteria. New small molecule antibiotics and anticancer agents that we have uncovered in these studies, as well as the modes of action of these metabolites, their distribution in the environment and improved methods for accessing them will be described.