Resveratrol, a valuable plant-derived polyphenolic compound with various bioactivities, has been widely used in nutraceutical industries. Microbial production of resveratrol suffers from metabolic burden and low malonyl-CoA availability, which is a big challenge for synthetic biology. Herein, we took advantage of coculture engineering and divided the biosynthetic pathway of resveratrol into the upstream and downstream strains. By enhancing the supply of malonyl-CoA via CRISPRi system and fine-tuning the expression intensity of the synthetic pathway genes, we significantly improved the resveratrol productivity of the downstream strain. Furthermore, we developed a resveratrol addiction circuit that coupled the growth of the upstream strain and the resveratrol production of the downstream strain. The bidirectional interaction stabilized the coculture system and increased the production of resveratrol by 74%. Moreover, co-utilization of glucose and arabinose by the coculture system maintained the growth advantage of the downstream strain for production of resveratrol throughout the fermentation process. Under optimized conditions, the engineered E. coli coculture system produced 204.80 mg/L of resveratrol, 12.8-fold improvement over monoculture system. This study demonstrates the promising potential of coculture engineering for efficient production of natural products from biomass.

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