Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin

Pharmaceutical monotherapies against human malaria have proven effective, although ephemeral, owing to the inevitable evolution of resistant parasites. Resistance to two or more drugs delivered in combination will evolve more slowly; hence combination therapies have become the preferred norm in the fight against malaria. At the forefront of these efforts has been the promotion of Artemisinin Combination Therapy, but despite these efforts, resistance to artemisinin has begun to emerge. In 2012, we demonstrated the efficacy of the whole plant (WP)—not a tea, not an infusion—as a malaria therapy and found it to be more effective than a comparable dose of pure artemisinin in a rodent malaria model. Here we show that WP overcomes existing resistance to pure artemisinin in the rodent malaria Plasmodiumyoelii. Moreover, in a long-term artificial selection for resistance in Plasmodium chabaudi, we tested resilience of WP against drug resistance in comparison with pure artemisinin (AN). Stable resistance to WP was achieved three times more slowly than stable resistance to AN. WP treatment proved even more resilient than the double dose of AN. The resilience of WP may be attributable to the evolutionary refinement of the plant’s secondary metabolic products into a redundant, multicomponent defense system. Efficacy and resilience of WP treatment against rodent malaria provides compelling reasons to further explore the role of nonpharmaceutical forms of AN to treat human malaria.The fight against malaria predates the discovery of its causative agent, and for centuries malaria-associated fever was treated using herbal remedies. In the West, quinine (Cinchona bark extract) was the only affordable treatment against malaria until Paul Ehrlich’s magic bullet concept was adopted and thousands of synthetic compounds were tested against malaria parasites. Very few of these compounds were effective and/or safe for human use, but in the 1930s chloroquine rose to ascendancy as a miracle cure for malaria (1). In the late 1950s, chloroquine was the main weapon used by the World Health Organization (WHO) in its Global Malaria Eradication Program (GMEP). Sadly, development of drug-resistant parasites and concomitant failure of chloroquine as the drug of choice led to the eventual demise of GMEP by the close of the 1960s. Following chloroquine’s failure, various antimalarial compounds were serially deployed, and each in its turn failed as parasites evolved resistance, thus leaving millions of malaria patients without affordable treatment.In the 1970s, artemisinin was discovered as a pure drug extracted from the plant Artemisia annua. In wide-scale clinical trials, pure artemisinin showed poor pharmacokinetic properties but nonetheless demonstrated potent antimalarial activity with a high safety profile (2). It was determined that artemisinin when modified to artesunate or artemether improved bioavailability and was more effective when used in combination with other antimalarial drugs, mainly mefloquine, which became known as Artemisinin Combination Therapy (ACT) (3). It was hoped that use of ACTs would minimize risk of drug resistance. However, in 2005 the earliest evidence of P. falciparum resistance to ACTs arose in Southeast Asia (4–8). The fight against malaria became critical once again when it became apparent that ACT might be following chloroquine’s path toward obsolescence with no affordable replacement in sight.We demonstrated the efficacy of the whole A. annua plant as a malaria therapy and found it to be more effective than a comparable dose of pure artemisinin in a rodent malaria model (9). WHO has cautioned against use of nonpharmaceutical sources of artemisinin because of the risk of delivering subtherapeutic doses that could exacerbate the resistance problem (10). This warning is valid given the low artemisinin content of juice extractions, teas, and infusion preparations of plant material used for most nonpharmaceutical plant-based therapies. However, the Whole Plant (WP) A. annua therapy that we have tested is not an extraction, a tea, or an infusion, but is based on oral consumption of the dried leaves of the whole plant. Based on our proof of principle in a rodent model, we postulate that with further development WP might provide a more abundant and affordable source of artemisinin-based therapy by eliminating the need for artemisinin extraction during manufacture.WP may be more effective than monotherapeutic artemisinin because WP may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity. This plant Artemisinin Combination Therapy (pACT) is the result of evolutionary refinement of the plant’s secondary metabolic products into a resilient and multicomponent defense system. As was demonstrated for other combination therapies, we hypothesized that a WP-based pACT would (i) overcome existing resistance to monotherapeutic pure artemisinin and (ii) increase the longevity of this therapy by delaying the onset of parasite resistance among wild types. Here, we tested these two hypotheses in two mouse malaria models, artemisinin-resistant Plasmodiumyoelii (strain: ART) and artemisinin-sensitive Plasmodium chabaudi (strain: ASS).