Sponsor
This work was supported by a National Health and Medical Research Council Investigator Award (GNT2016391) to GMcF. Synthesis of T111 was supported by the NIH/NIAID (award R01AI158533), DOD/PRMRP 562 (award PR219491/W81XWH2210494), and VA BLRD (award 1I01BX005674).
Published In
International Journal for Parasitology
Document Type
Pre-Print
Publication Date
5-29-2025
Subjects
Malaria -- Prevention
Abstract
A decade-long decline in malaria cases has plateaued, primarily due to parasite drug resistance and mosquito resistance to insecticides used in bed nets and indoor residual spraying. Here, we explore the innovative control strategy targeting Plasmodium with antimalarials during the mosquito stages. This strategy has the potential to reduce the risk of resistance emerging because a relatively small population of parasites within the mosquito is subject to selection. After validating mosquito feeding strategies, we screened a range of parasiticidal compounds by feeding them to mosquitoes already infected with mouse malaria (P. berghei). Three antimalarials showed activity against P. berghei in mosquitoes, apparently targeting specific stages of P. berghei development during transmission. Borrelidin, a threonyl-tRNA synthetase inhibitor, significantly reduced P. berghei sporozoite numbers. Azithromycin, an antibiotic targeting apicoplast protein synthesis, significantly lowered sporozoite infectivity in mice. T111, a next generation compound targeting the parasite electron transport chain, reduced sporozoite numbers in P. berghei at equivalent concentrations to the gold standard electron transport chain inhibitor, atovaquone. T111 also prevented sporozoite production in mosquitoes infected with human malaria, P. falciparum, even after very short exposure times. Encouragingly, T111 remained efficacious after being freeze-dried onto a substrate and later reconstituted with water, suggesting this compound would be effective in easy-to-distribute-and-deploy transmission control devices. Our findings suggest that several antimalarials can be used to target mosquito-stage parasites via sugar baits and limit malaria transmission. Importantly, mosquito feeding of antimalarials could vastly increase the range of potentially useful parasiticidal compounds to include those failing to meet the exacting standards required for human antimalarial drugs, potentially improving malaria control for minimal cost.
Rights
Copyright (c) 2025 The Authors
This work is licensed under a Creative Commons Attribution 4.0 International License.
Locate the Document
DOI
10.1016/j.ijpara.2025.05.005
Persistent Identifier
https://archives.pdx.edu/ds/psu/43681
Publisher
Elsevier BV
Citation Details
Farrell, S. N., Cozijnsen, A., Mollard, V., Kancharla, P., Dodean, R. A., Kelly, J. X., McFadden, G. I., & Goodman, C. D. (2025). Identifying antimalarials that disrupt malaria parasite transmission when fed to the mosquito. International Journal for Parasitology.
Description
This is the author’s version of a work that was accepted for publication. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published as: Identifying antimalarials that disrupt malaria parasite transmission when fed to the mosquito. International Journal for Parasitology.