Insecticide-based vector control remains the cornerstone of malaria prevention, averting approximately 1.2 billion cases between 2000 and 2025. These interventions primarily reduce transmission by killing mosquitoes; however, widespread reliance on a limited number of compounds has driven the emergence of insecticide resistance. This has prompted the development of new insecticides with novel modes of action. Notably, the pyrrole insecticide chlorfenapyr has been shown to affect both the mosquito vector and the malaria parasite, suggesting that compounds with dual activity could provide an additional strategy to suppress transmission. Here, we present a medium-throughput discovery pipeline that integrates in vitro Plasmodium sporozoite motility assays with machine-learning-based analysis, alongside in vivo exposure of infected Anopheles mosquitoes and quantification of parasite development. Screening 32 insecticidal chemistries identified five compounds that significantly impaired sporozoite motility, including three avermectin endectocides, the mitochondrial complex III inhibitor hydramethylnon, and tralopyril, the active form of chlorfenapyr. Several compounds transiently increased motility, indicating that parasite physiology is frequently influenced by insecticide exposure. In vivo exposure to abamectin reduced parasite numbers in both the haemolymph and salivary glands and impaired productive motility. Importantly, this inhibition was confirmed in Plasmodium falciparum-infected mosquitoes, where exposure significantly reduced salivary gland invasion. These findings reveal that parasite-directed activity among insecticides may be more common than previously appreciated and demonstrate a scalable approach to identify compounds capable of simultaneously killing mosquitoes and suppressing parasite transmission.
Boehmert, A. L., Sturm, M., Portwood, N. M., Maeurer, J. B., Frischknecht, F., Hamprecht, F., Ingham, V. A.
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