Genomes to Natural Products and Back

Microbial life has evolved a vast number of pharmaceutically relevant natural products, and sequencing efforts indicate that nearly 90% remain undiscovered. Prediction of these chemical structures from genetic material facilitates their discovery, albeit in a tedious and inherently inaccurate manner that prevents the automated detection of desired compounds in complex culture extracts. Here, we present a genome-guided natural products discovery tool to automatically predict, combinatorialize, and identify these genetically-encoded natural products in LC-MS/MS data of crude extracts at a rate in-keeping with high-throughput sequencing and screening. We detail the directed identification and isolation of five genetically-predicted natural products using our Genome-to-Natural products Platform (GNP), including three novel scaffolds and a cryptic lipopeptide. By rapidly identifying targeted molecules, this integrated and automated platform provides a means for realizing the potential of genetically-encoded natural products in a post-genomic era. Just like a genomes to natural products is needed so to is a natural products to genomes platform needed and this talk will communicate our work toward this methodology to link ‘cryptic’ clusters to known products.