Artemisinin (AN), produced by the plant Artemisia annua L., is a proven therapeutic for treating malaria and also for treatment of a large range of bacterial, viral and parasitic diseases, and cancers. While AN has high value as a therapeutic, its production is only cost effective when harvested from field grown plants. Understanding biosynthetic control of this important terpenoid drug is crucial to meeting the growing worldwide demand. Recently we showed that plants subjected to reactive oxygen stress produce higher levels of AN and its precursors. Since this phenomenon has the potential to link a variety of established AN elicitors in a unified model, we propose investigating reactive oxygen stress as a key regulator of AN biosynthesis. Our 3 objectives are: 1. Investigation of the relative expression levels of early (HMGR, FPS) and late dedicated (ADS, CYP71AV1, DBR2, ALDH1) genes as plants are subjected to diverse sources of oxidative stress, including photo, drought, and chemically induced oxidation. These data would serve to identify a transcriptional basis for ROS induction of AN production. 2. Compare metabolic profiles and the redox state of plants under normal and oxygen stressed growing conditions. Measuring key metabolic intermediates allows us to form a preliminary metabolic balance map showing key points of change upon ROS-induced perturbations to help further elucidate the ROS role in the putative non-enzymatic last step of AN biosynthesis and metabolite balance control not readily identifiable through transcript analysis. 3. Investigate and demonstrate in soil-grown plants a process for increasing AN production through the induction of oxidative stress by both biotic and abiotic means that will allow for optimizing production of AN while simultaneously allowing for maximum plant growth. This will further correlate potentially simple methods that could be employed immediately to induce mild oxidative stress for over production of artemisinin in soil-grown plants. These results will further our fundamental understanding of the biosynthesis of artemisinin in A. annua and will further our ability to enhance its production to meet the ever growing therapeutic demand.

Public Health Relevance

Malaria and the neglected tropical diseases addressed in our proposal account for >500 million infections and upwards of 2 million deaths. Artemisinin has been shown to be effective against all of these diseases, but the drug is in desperately short supply to treat even malaria. Our studies on reactive oxygen will facilitate a better understanding of the last steps in the biosynthetic pathway thereby enhancing the potential to increase the drug produced in the plant.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Jones, Warren
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Worcester Polytechnic Institute
Schools of Engineering
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Weathers, Pamela J; Elfawal, Mostafa A; Towler, Melissa J et al. (2014) Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice. J Ethnopharmacol 153:732-6
Weathers, Pamela J; Jordan, Nikole J; Lasin, Praphapan et al. (2014) Simulated digestion of dried leaves of Artemisia annua consumed as a treatment (pACT) for malaria. J Ethnopharmacol 151:858-63
Nguyen, Khanhvan T; Towler, Melissa J; Weathers, Pamela J (2013) The effect of roots and media constituents on trichomes and artemisinin production in Artemisia annua L. Plant Cell Rep 32:207-18
Weathers, Pamela J; Towler, Melissa J (2012) The flavonoids casticin and artemetin are poorly extracted and are unstable in an Artemisia annua tea infusion. Planta Med 78:1024-6
Weathers, Pamela J; Arsenault, Patrick R; Covello, Patrick S et al. (2011) Artemisinin production in Artemisia annua: studies in planta and results of a novel delivery method for treating malaria and other neglected diseases. Phytochem Rev 10:173-183
Nguyen, Khanhvan T; Arsenault, Patrick R; Weathers, Pamela J (2011) Trichomes + roots + ROS = artemisinin: regulating artemisinin biosynthesis in Artemisia annua L. In Vitro Cell Dev Biol Plant 47:329-338
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Sivakumar, Ganapathy; Liu, Chunzhao; Towler, Melissa J et al. (2010) Biomass production of hairy roots of Artemisia annua and Arachis hypogaea in a scaled-up mist bioreactor. Biotechnol Bioeng 107:802-13
Arsenault, Patrick R; Vail, Daniel R; Wobbe, Kristin K et al. (2010) Effect of sugars on artemisinin production in Artemisia annua L.: transcription and metabolite measurements. Molecules 15:2302-18
Mannan, Abdul; Liu, Chunzhao; Arsenault, Patrick R et al. (2010) DMSO triggers the generation of ROS leading to an increase in artemisinin and dihydroartemisinic acid in Artemisia annua shoot cultures. Plant Cell Rep 29:143-52

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