A New Biosensor for Stilbenes and a Cannabinoid Enabled by Genome Mining of a Transcriptional Regulator

In vivo biosensors are powerful tools for metabolic engineering and synthetic biology applications. However, the development of biosensors is hindered by the limited number of characterized transcriptional regulators. The versatile sensing abilities of microbes and genome sequences available hold great potential for developing novel biosensors via genome mining for new transcriptional regulators. Here we report the development and engineering of a new stilbene-responsive biosensor discovered by mining the Novosphingobium aromaticivorans DSM 12444 genome. The biosensor can distinguish resveratrol from its precursors, p-coumaric acid and trans-cinnamic acid. Remarkably, it can detect other biologically active stilbenes with resorcinol groups, and cannabidiolic acid with a β-resorcylic acid functional group. When coupled to resveratrol biosynthesis enzymes, the biosensor can sense altered resveratrol production in cells, demonstrating a 667-fold enrichment in one round of fluorescence-activated cell sorting. Our biosensor will be potentially applicable to metabolic engineering of microbial cell factories for production of stilbenes and cannabinoids.