In many regions of the world, strains of Plasmodium have emerged that are resistant to the current arsenal of antimalarial therapeutics. Artemisinins, terpenoid compounds derived from traditional Chinese medicines used for centuries, have been acclaimed as the next generation of antimalarial drugs because they show little or no cross-resistance with existing antimalarials. While inexpensive by Western standards, artemisinin based treatments remain prohibitively expensive to those in the developing world who need them most. The long term goal of this SBIR-at-NIAID project is to develop an artemisinin production process utilizing a biosynthetically produced synthon, artemisinic acid. Methods for the synthesis of artemisinin from artemisinic acid currently exist, but are not utilized due to the cost of extracting the precursor. This Phase I project will address this problem by proving the feasibility of producing artemisinic acid via a bacterial fermentation. Building on previous work which enabled the production of the artemisinic acid precursor, amorphadiene, at high levels, we will build a production strain that is able to produce economically relevant levels of amorphadiene. We will also isolate, clone, and express the genes, likely encoding cytochrome P450s, responsible for the conversion of amorphadiene to artemisinic acid. Additionally, we will engineer the machinery for efficient catalysis by P450s in E. coli. This research, conducted in collaboration with the University of California, could eventually lead to reductions in the cost of artemisinin based treatments by a factor of 3 or more. This technology could also result in the development of many promising new terpene-based drugs produced at a lower cost to consumers, reduced time to market, and to decreased effect on the environment, in terms of destruction of natural resources and the release of synthetic chemical effluents.
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Thesaurus Terms: Antimalarial Agent, Bioreactor, Drug Design /Synthesis /Production, Fermentation, Microorganism Mass Culture Cost Effectiveness, Cytochrome P450, Enzyme Activity, Enzyme Mechanism Escherichia Coli, Biotechnology
