Developing an industrial artemisinic acid fermentation process to support the cost-effective production of antimalarial artemisinin-based combination therapies.

Artemisinin-based combination therapies (ACTs) are currently unaffordable for many of the people who need them most. A major cost component of ACTs is the plant-derived artemisinin. A fermentation process for a precursor to artemisinin might provide a viable second source to stabilize the artemisinin supply and therefore reduce price. The heterologous production of artemisinic acid, an artemisinin precursor, by Saccharomyces cerevisiae was improved 25-fold from a 100 mg/L flask process to a 2.5 g/L process in bioreactors. A defined medium fed-batch process with galactose as the carbon source and inducer was developed, with titers of 1.3 g/L. In this strain ERG9 was controlled with promoter Pmet3 so that methionine repressed the sterol biosynthesis pathway and increased precursor availability for artemisinic acid biosynthesis. Addition of methionine to the process increased artemisinic acid titers to 1.8 g/L. A dissolved oxygen-stat algorithm was developed, which simultaneously controlled the agitation and feed pump. This improved process control and increased titers to 2.5 g/L.