Transmissibility of clinically relevant atovaquone-resistantPlasmodium falciparumby anopheline mosquitoes

Abstract

Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria chemical vaccine, combining the efficacy of a drug (like atovaquone) with the durability of a biological vaccine. Of concern, however, is the possible selection and transmission of drug-resistant parasites. We addressed this question by generating clinically relevant, highly atovaquone-resistant, Plasmodium falciparum mutants competent to infect mosquitoes. Isogenic paired strains, that differ only by a single Y268S mutation in cytochrome b, were evaluated in parallel in southeast Asian (Anopheles stephensi) or African (Anopheles gambiae) mosquitoes, and thence in humanized mice. Fitness costs of the mutation were evident along the lifecycle, in asexual parasite growth in vitro and in a progressive loss of parasites in the mosquito. In numerous independent experiments, microscopic exam of salivary glands from hundreds of mosquitoes failed to detect even one Y268S sporozoite, a defect not rescued by coinfection with wild type parasites. Furthermore, despite uniformly successful transmission of wild type parasites from An. stephensi to FRG NOD huHep mice bearing human hepatocytes and erythrocytes, multiple attempts with Y268S-fed mosquitoes failed: there was no evidence of parasites in mouse tissues by microscopy, in vitro culture, or PCR. These studies confirm a severe-to-lethal fitness cost of clinically relevant atovaquone-resistant P. falciparum in the mosquito, and they significantly lessen the likelihood of their transmission in the field.

Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes

“…Ideally, the partner compounds should not only be safe, cheap, compatible, and effective but also be refractory to the spread of resistance, thus prolonging the life of the frontline compound whilst also minimising the risk of selecting for multidrug resistance. Atovaquone is an antimalarial refractory to the spread of resistance (Balta et al, 2023;Goodman et al, 2016). Atovaquone resistance is unable to be transmitted because resistant parasites with mutations in the mitochondrially-encoded cytochrome b suffer fitness deficits during the mosquito phase of their life cycle where they rely on higher rates of mitochondrial electron transport (Goodman et al, 2017;Goodman et al, 2016).…”

“…Atovaquone is an antimalarial refractory to the spread of resistance (Balta et al, 2023; Goodman et al, 2016). Atovaquone resistance is unable to be transmitted because resistant parasites with mutations in the mitochondrially-encoded cytochrome b suffer fitness deficits during the mosquito phase of their life cycle where they rely on higher rates of mitochondrial electron transport (Goodman et al, 2017; Goodman et al, 2016).…”