Natural products, also known as secondary metabolites, and their synthetic derivatives have a wide range of applications in medicine, veterinary practice, agriculture and industry. Despite the incredible successes, the field of natural product research is facing two major challenges, the low rate of new discoveries and the limited chemical supply, impeding the continuous success. On the other hand, recent advances of DNA sequencing techniques illuminate the extraordinarily rich potential of natural products by microbial strains, of which we have only tapped the surface. The genetic makeup of natural products offers new opportunities to the discovery and production of valuable chemicals, propelled by the development of synthetic biology, potentially addressing the above two major challenges. Herein, I present our recent studies in the production of natural products and analogs, specifically thaxtomins, using both in vitro and in vivo synthetic biology approaches. Thaxtomins are a group of phytotoxic diketopiperazines produced by tens of plant pathogenic Streptomyces strains and have received considerable attention as bioherbicides, which EPA has approved for field use. However, the low yield of these compounds in native producers limits their economical agricultural applications. To this end, we genetically engineered five nonnative hosts to overproduce thaxtomins. We discovered that both the context of the biosynthetic gene cluster and the genetic background of hosts significantly influence the thaxtomin productivity, an important finding aiding to producing natural products from their gene clusters. Further genetic studies improved the productivity of thaxtomins in S. albus to a sub-gram per litter level, produced novel bioactive analogs, and developed a cost-effective production route by refactoring the gene cluster. To further free biological constrains for chemical production, we reconstructed thaxtomin biosynthesis in vitro. This work successfully produced over 120 novel analogs in a biocombinatorial manner and uncovered new rules to control chemical diversity generation. Overall, our studies reveal critical new insights into the discovery and production of natural products using synthetic biology approaches, facilitating the translation of genomes into chemicals.

Production of bioherbicides by in vivo and in vitro synthetic biology approaches

2019 Spring National Meeting

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