Microorganisms are a major source of new therapeutic agents.  Sequenced genomes and metagenomes provide a tremendously rich source for discovery of novel gene clusters involved in natural product biosynthesis.  However, only a tiny fraction of those putative natural product biosynthetic gene clusters have been characterized.  To address this limitation, my group has developed a new genomics-driven, synthetic biology enabled strategy to discover and produce novel natural products from sequenced genomesand metagenomes.  Largely based on our recently developed DNA assembler method, this new strategy refactors the entire biosynthetic pathway in a heterologous host.  As proof of concept, we successfully refactored the silent spectinabilin pathway from Streptomyces spectabilis in Streptomyces lividans and activated a cryptic pathway containing a polyketide synthase-non-ribosomal peptide synthetases from Streptomyces grieseus to obtain a novel natural product. This strategy represents a powerful synthetic biology tool for discovery and production of novel natural products and pathway engineering.

Discovery of novel natural products by refactoring cryptic pathways

245th National Meeting (2013)

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