Discovery of Antibiotics from Soil Microbiomes Using Metagenomics

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Project Summary: Bacterial natural products have a long history of serving as lead structures for the development of new therapeutically relevant small molecules. Despite the tremendous early success of bacterial natural product discovery programs, both academic and industrial drug screening efforts have largely deprioritized natural products in recent years due to unacceptably high rediscovery rates, which were often taken as an indication that nature had few novel small molecules left for us to identify. Extensive sequencing of both bacterial genomic and metagenomic DNA indicates that this is, in fact, not the case. Instead, it appears that we have just begun to scratch the surface of the structural and functional diversity of small molecules encoded by the global microbiome. In most environments uncultured bacteria still significantly outnumber their cultured counterparts, and even when it is possible to grow bacteria in the laboratory they usually only express a small subset of their natural product biosynthetic gene clusters. My research group is focused on the development of culture-independent (metagenomic) approaches for identifying novel natural products encoded provides a means of accessing this large fraction of previously inaccessible biosynthetic diversity. In these studies, the need to culture bacteria is circumvented by extracting DNA directly from environmental samples and cloning it into easily cultured bacteria. This proposal is designed to continue our development of culture-independent methods for accessing the natural products encoded in soil metagenomes and to increasingly apply these methods to the discovery and characterization of new bioactive small molecules. In particular, our studies will include the development of new sequence-based and functional metagenomic screening methods as well as the use of heterologous expression and synthetic bioinformatic natural product discovery approaches to generate novel small molecules from soil metagenome derived biosynthetic gene clusters. Method develop studies will be focus on overcoming key technical hurdles to enable the more efficient and higher throughput discovery of structurally and mechanistically different natural products from metagenomes using both bioinformatic and unbiased functional screening approaches. As with traditional natural product discovery programs, our ultimate goal is to identify bioactive small molecules that have the potential to be used as lead structures for the development of novel therapeutics. Although our metagenomic methods can be applied to the identification of compounds that can target almost any disease, we will primarily focus on the discovery of new antibiotics. This choice is driven by the long history of natural products being the most productive source of potent antibiotics with unique modes of actions and the clear biomedical need for new antibiotics that are effective against clinically relevant, multi-drug resistant, Gram-positive and Gram-negative pathogens.