Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin - PubMed (original) (raw)

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

Mostafa A Elfawal et al. Proc Natl Acad Sci U S A. 2015.

Abstract

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 Plasmodium yoelii. 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.

Keywords: Plasmodium; artemisinin; drug resistance; evolution; malaria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

AN-resistant P. yoelii (ART) single-dose WP and AN treatments. Arrow indicates time of treatment. (A) Mean parasitemia (±SD) for (light green) WPHI-treated and (dark blue) ANHI-treated mice; both treatments correspond to a total artemisinin dose of 120 mg/kg, but WPHI is delivered as whole dried plant as opposed to ANHI, which is delivered as pure drug. (B) Mean parasitemia (±SD) for (light green) WPLO-treated and (light blue) ANLO-treated mice receiving the equivalent of 24 mg/kg of artemisinin. Placebo control (red) received only mouse chow. All treatements and control were run simultaneously, but the plots are presented separately by dosage to show comparisons between delivery methods.

Fig. 2.

Fig. 2.

AN-resistant P. yoelii (ART) curative treatment. Mice were infected with AN-resistant P. yoelii (ART) and treated with either ANHI or WPHI daily for 9 consecutive days starting on day 2 postinfection. Blue line indicates mean parasitemia of ANHI-treated mice (n = 6) and green line represents means parasitemia of WPHI with error bars representing SD. Days with significant difference in mean parasitemia are indicated with “**” (P < 0.01).

Fig. 3.

Fig. 3.

Experimental evolution of drug resistance in P. chabaudi (ASS) following the 2% relapse technique. Selection for resistance in P. chabaudi required more passages in mice administered WP (green) than in mice receiving AN (blue). Drug efficacy (y axis) is measured as the difference in time to reach 2% infected red blood cells between treated and untreated animals. Consistent with evolution of resistance, drug efficacy (2%DT) waned over time for all groups. However, AN ceased impairing parasite replication by passage 16, whereas the equivalent dose of WP never resulted in total loss of efficacy. When 2%DT for “AN (100 mg/kg)” reached zero, the dose of AN was doubled (200 mg/kg), but this only temporarily restored drug efficacy as stable resistance to that dose was achieved by passage 46.

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