Using microbial co-cultures involving Yarrowia lipolytica to produce sesquiterpenoids

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The central aim of this project is utilising various biological co-culture engineering and related techniques to achieve high and industrially relevant production of sesquiterpenoids in the yeast Yarrowia lipolytica. Sesquiterpenoids are types of high-value terpenoids with various uses in medicine such as in the treatment of cancer, neurodegenerative diseases, inflammation, wound healing and others. Yarrowia lipolytica has been identified as a potential high producer of terpenoids. Cooperation of different microbial species as well as specialisation within the single-species community are emerging metabolic engineering strategies to increase the biotechnological productivity of microbes. My project contains several steps towards the efficient community-based production of sesquiterpenoids: 1) Use cyanobacteria or algae engineered to secrete sucrose in a community with Yarrowia lipolytica to feed it while consuming a waste product of Yarrowia, CO22) Engineer Yarrowia lipolytica metabolism by genetic modifications to overproduce sesquiterpenoids. The major strategy would be overproducing pathway enzymes leading to the final product and repressing the other pathway branches. 3) Creating a single-species Yarrowia community. Yarrowia produces citric acid as a waste product which decreases the carbon use towards the desired product significantly. However, Yarrowia is also able to utilise citric acid. I aim to engineer both strains to produce the final sesquiterpenoid product but one of the Yarrowia strains consuming the citric acid waste. 4) I would aim to combine the 1st and 2nd point into cyanobacteria-yeast intracellular interaction. Cyanobacteria would be releasing sucrose and sesquiterpenoid intermediates into Yarrowia cytosol to get converted into the final products. 5) Additional avenues to explore: - Computational modelling of community behaviour and application of existing models- Constructing automated directed evolution devices to screen the best performing communities and allow those to adapt further- Analysis of what happens inside the community member cells- Embedding the co-cultures into biomaterials to produce medically-relevant compounds into wounds