title: Eliciting renal failure in mosquitoes with a small-molecule inhibitor of inward-rectifying potassium channels.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Raphemot
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Rouhier
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: Rocco D
authors.initials: RD
authors.lastname: Gogliotti
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lovell
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Hine
authors.forename: Dhairyasheel
authors.initials: D
authors.lastname: Ghosalkar
authors.forename: Anthony
authors.initials: A
authors.lastname: Longo
authors.forename: Klaus W
authors.initials: KW
authors.lastname: Beyenbach
authors.forename: Jerod S
authors.initials: JS
authors.lastname: Denton
authors.forename: Peter M
authors.initials: PM
authors.lastname: Piermarini
mesh_terms: D000330:Aedes / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D000818:Animals; D000852:Anopheles / Q000254:growth & development / Q000378:metabolism; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003465:Culex / Q000254:growth & development / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006458:Hemolymph / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019476:Insect Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology; D008317:Malpighian Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: C585410:1-(3-benzyl-2-imino-2,3-dihydro-1H-benzo(d)imidazol-1-yl)-3-(p-tolyloxy)propan-2-ol; D001562:Benzimidazoles; D007097:Imines; D019476:Insect Proteins; D007306:Insecticides; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011188:Potassium