Biosynthesis of resveratrol by co-culturing engineered Yarrowia lipolytica strains

Resveratrol (3,4',5-trihydroxystilbene) and its derivatives (e.g., pterostilbene, piceatannol, and viniferin) are naturally occurring compounds found in plants and have various medicinal properties, including anti-inflammatory, antimicrobial, anti-cancer and many other activities. Therefore, they are commercialised as components of many medicines, nutritional supplements, healthy foods, and cosmetics. However, plants typically have low concentrations of resveratrol (e.g., 5.1 μg/g in peanut and 3.9 mg/g in Rheum rhaponticum). Extracting resveratrol from plants is a traditional method with notable drawbacks, including long growth times (several years), high costs, low yields, land and labor waste, and pollution of the environment. The chemical synthesis of resveratrol involves complex steps, uses hazardous solvents, and generates toxic byproducts. Due to these reasons, biotechnological production of resveratrol by recombinant microorganisms is a promising strategy to solve the above issues. The current production of resveratrol synthesised by mono-culturing yeast remains relatively low, with productions in shake flasks being less than 1 g/L. Microbial co-culture is a cooperation strategy where microorganisms survive by feeding on the metabolic products of neighbors. This approach alleviates the significant metabolic burden associated with engineering a single strain to handle the entire biosynthetic pathway of metabolites. It promises to increase final production compared to the mono-culture. This proposed study relates to a novel approach in resveratrol biosynthesis by Y. lipolytica, which will address a critical question in today's resveratrol biosynthesis research: can the co-culture of Y. lipolytica engineered strains using lignocellulose as a sustainable carbon source significantly improve resveratrol production and promote the industrialisation of resveratrol biosynthesis in Europe?