Farrell Sarah N, Cozijnsen Anton, Mollard Vanessa, Kancharla Papireddy, Dodean Rozalia A, Kelly Jane X, McFadden Geoffrey I, Goodman Christopher D
School of Biosciences, The University of Melbourne, Parkville, VIC 3010, Australia.
School of Biosciences, The University of Melbourne, Parkville, VIC 3010, Australia.
Int J Parasitol. 2025 May 29. doi: 10.1016/j.ijpara.2025.05.005.
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.
疟疾病例长达十年的下降趋势已趋于平稳，主要原因是寄生虫产生了耐药性，以及蚊子对蚊帐和室内滞留喷洒中使用的杀虫剂产生了抗性。在此，我们探索了一种创新的控制策略，即在蚊子阶段使用抗疟药物靶向疟原虫。这种策略有可能降低耐药性出现的风险，因为蚊子体内相对较少的寄生虫群体处于选择压力之下。在验证了蚊子的取食策略后，我们通过将一系列杀寄生虫化合物喂给已感染鼠疟（伯氏疟原虫）的蚊子来进行筛选。三种抗疟药物对蚊子体内的伯氏疟原虫显示出活性，显然是针对伯氏疟原虫传播过程中的特定发育阶段。硼替佐米，一种苏氨酰 - tRNA合成酶抑制剂，显著减少了伯氏疟原虫子孢子数量。阿奇霉素，一种靶向顶质体蛋白合成的抗生素，显著降低了子孢子对小鼠的感染性。T111，一种靶向寄生虫电子传递链的新一代化合物，在与金标准电子传递链抑制剂阿托伐醌相同的浓度下，减少了伯氏疟原虫的子孢子数量。T111甚至在极短的暴露时间后，也能阻止感染人类疟疾（恶性疟原虫）的蚊子产生子孢子。令人鼓舞的是，T111冻干到基质上并用水复溶后仍保持有效，这表明该化合物在易于分发和部署的传播控制装置中会有效。我们的研究结果表明，几种抗疟药物可通过糖饵靶向蚊子阶段的寄生虫并限制疟疾传播。重要的是，给蚊子喂食抗疟药物可能会大大增加潜在有用的杀寄生虫化合物的范围，包括那些未达到人类抗疟药物严格标准的化合物，有可能以最低成本改善疟疾控制。
