Antimalarials in mosquitoes overcomeAnophelesandPlasmodiumresistance to malaria control strategies

Abstract

The spread of insecticide resistance in Anopheles mosquitoes and drug resistance in malaria parasites is contributing to a global resurgence of malaria, and the generation of control tools that can overcome these issues is an urgent public health priority. We recently demonstrated that the transmission of Plasmodium falciparum parasites by Anopheles gambiae can be efficiently blocked when female mosquitoes contact the antimalarial atovaquone deposited on a treated surface, with no negative consequences on mosquito fitness. Here, we demonstrate that the transmission-blocking efficacy of mosquito-targeted atovaquone is maintained when highly insecticide resistant, field-derived Anopheles mosquitoes are exposed to this antimalarial, indicating that insecticide resistance mechanisms do not interfere with drug function. Moreover, this approach prevents transmission of field P. falciparum isolates, including an artemisinin resistant Kelch13 C580Y mutant, demonstrating that this strategy could prevent the spread of parasite mutations that induce resistance to front-line antimalarials. Finally, we show that ingestion of atovaquone in sugar solution is highly effective at limiting parasite development, including in ongoing infections. These data support the use of mosquito-targeted antimalarial interventions to potentiate and extend the efficacy of our best malaria control tools.

Transmissibility of clinically relevant atovaquone-resistantPlasmodium falciparumby anopheline mosquitoes

“…At least three other laboratories have evaluated the survival in mosquitoes, and in some cases transmissibility, of atovaquone-resistant parasites (22)(23)(24). None of these reports include a clinically relevant P. falciparum Y268 mutant.…”

“…Furthermore, atovaquone resistance of in vitro-generated mutants is substantially lower (typically 100-to 1000-fold) than that of the clinically relevant Y268N/S/C. The dichotomy between in vitro and clinical mutants assumed greater importance with intriguing reports that the development of atovaquone-resistant parasites in mosquitoes is impaired or halted (22)(23)(24), suggesting their transmission may be limited in the field. Unfortunately, these studies have not included an evaluation of the Y268 mutants of P. falciparum that pertain to clinical drug resistance.…”