Discovery of Novel Natural Products via Synthetic Biology

Microorganisms are a major source of new therapeutic agents. My group has been developing new genomics-driven, synthetic biology-enabled methods to discover and produce novel natural products from sequenced genomes and metagenomes. One strategy is to refactor target cryptic gene clusters in heterologous hosts. As proof of concept, we used this strategy to awaken the silent polyketide spectinabilin pathway from Streptomyces spectabilis in Streptomyces lividans and activate a cryptic pathway containing a polyketide synthase-non-ribosomal peptide synthetases from Streptomyces grieseus in Streptomyces lividans, which led to the discovery of two novel tetramic acid natural products that have never been reported in literature. To increase the throughput, we are establishing a fully integrated robotic system to automate all the steps in gene cluster refactoring and product detection. Another strategy is to activate the target cryptic gene clusters in their native hosts by knocking-in strong promoters upstream of the target cryptic gene clusters. Recently, we developed a CRISPR/Cas9 based system for rapid multiplex genome editing of Streptomyces strains, demonstrating targeted chromosomal deletions in three different Streptomyces species and of various sizes (ranging from 20 bp to 30 kb) with efficiency ranging from 70-100%. We are currently adapting this system for activating multiple cryptic gene clusters in several Streptomyces species.