What are we ‘mining' for? Massively multiplexed activity metabolomics for natural product discovery

Methods for genomics-enabled natural product discovery are developing at a rapid rate and it now appears that a substantial fraction of previously inaccessible microbial natural products will soon become available.  In this context, this presentation will focus on two aspects. (1) We will describe our recent progress in the analysis of large complex metabolomic data sets of native producers of microbial secondary metabolites and antibiosis of pathogens. This work extends the “shoot first ask questions later,” model of genome mining that is now unleashing substantial new chemical diversity. (2) Due to recent successes in stimulating the native and heterologous production of secondary metabolites, new molecule discovery will no longer be the rate-limiting in natural product drug discovery pipelines. We strongly feel that the next phase in this technology arc will be in the re-imagination of how tools in metabolomics, (and other high-content biological data acquisition), can be applied to understanding the roles of natural products in human biology and chemical ecology. Accomplishing this will require a wholesale shift from target-based bioassay to multiplexed analysis and management of large complex data sets. The second theme of this presentation will be our laboratory’s recent progress in developing new methods to shift the focus of discovery back to biological activity.