Eliciting Renal Failure in Mosquitoes with a Small-Molecule Inhibitor of Inward-Rectifying Potassium Channels

Mosquito-borne diseases such as malaria and dengue fever take a large toll on global health. The primary chemical agents used for controlling mosquitoes are insecticides that target the nervous system. However, the emergence of resistance in mosquito populations is reducing the efficacy of available insecticides. The development of new insecticides is therefore urgent. Here we show that VU573, a small-molecule inhibitor of mammalian inward-rectifying potassium (Kir) channels, inhibits a Kir channel cloned from the renal (Malpighian) tubules of Aedes aegypti (AeKir1). Injection of VU573 into the hemolymph of adult female mosquitoes (Ae. aegypti) disrupts the production and excretion of urine in a manner consistent with channel block of AeKir1 and renders the mosquitoes incapacitated (flightless or dead) within 24 hours. Moreover, the toxicity of VU573 in mosquitoes (Ae. aegypti) is exacerbated when hemolymph potassium levels are elevated, suggesting that Kir channels are essential for maintenance of whole-animal potassium homeostasis. Our study demonstrates that renal failure is a promising mechanism of action for killing mosquitoes, and motivates the discovery of selective small-molecule inhibitors of mosquito Kir channels for use as insecticides.以疟疾、登革热为代表的蚊媒疾病，对全球公共卫生造成了沉重负担。当前用于蚊虫防控的主流化学药剂为靶向昆虫神经系统的杀虫剂。然而，蚊虫种群抗药性的出现正不断削弱现有杀虫剂的防控效果，因此研发新型杀虫剂迫在眉睫。本研究证实，VU573——一种针对哺乳动物内向整流钾（inward-rectifying potassium, Kir）通道的小分子抑制剂——能够抑制从埃及伊蚊（Aedes aegypti）肾脏（马氏管）中克隆得到的Kir通道（AeKir1）。将VU573注射至成年雌性埃及伊蚊的血淋巴后，其尿液的生成与排泄过程会受到干扰，这一现象与AeKir1通道被阻断后的效应相符，且能在24小时内使蚊虫丧失行动能力（无法飞行或死亡）。此外，当血淋巴钾离子水平升高时，VU573对埃及伊蚊的毒性会增强，这表明Kir通道对于维持整体动物的钾离子稳态至关重要。本研究证实，肾功能衰竭可作为一种极具潜力的灭蚊作用机制，同时也推动了靶向蚊虫Kir通道的选择性小分子抑制剂的研发，以用作新型杀虫剂。