Resveratrol is a type of stilbene polyketite found in small quantities in plants. Recently, resveratrol has been demonstrated to increase the life-span of many organisms and is being tested as a new therapeutic against diseases associated with aging, such as diabetes and obesity. The minute quantities of stilbenes in plants hinder the development of inexpensive pharmaceuticals. In the present work, Escherichia coli was engineered to synthesize plant-specific stilbenes and their derivatives that do not exist in nature. The capacity of synthesizing stilbenes from the recombinant E. coli was initially low. The overcoming of this bottleneck was two folds. First, we designed biosynthetic enzyme analogues to search for chimeras that robustly catalyzed stilbene biosynthesis in the microorganism. Second, to accelerate the in vivo reaction rate, fluxes toward the malonyl-CoA backbone was increased. Introduction of a foreign carbon assimilation pathway increased product synthesis. However, high-level synthesis was only achieved through partial repression of lethal metabolic targets. These targets were mapped by a constructed in silico metabolism and gene deletion routines. Other gene targets that result in improvement of stilbene biosynthetic phenotype were also identified. Overall, through these strategies, the E. coli factory was capable of stilbene production in high-levels. Robust synthesis of the various non-natural molecules also allowed the structure-function analysis of inhibitory properties against digestive enzymes responsible of glucose assimilation. A stilbene derivative that exhibited higher potency to inhibit digestive enzymes than a currently prescribed drug was identified.

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