An insecticide resistance-breaking mosquitocide targeting inward rectifier potassium channels in vectors of Zika virus and malaria.

Daniel R Swale,Jerod S Denton,Jeffrey R Bloomquist,Edna Alfaro Inocente,Liu Yang,Darren W Engers,Corey R Hopkins,Reed M Johnson,Sean R Bollinger,Fariba Kanga,Peter M Piermarini,Emily Days,Aaron Gross

doi:10.1038/srep36954

Abstract

Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae.) aegypti Kir1 channels that incapacitates adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively) following topical application. VU041 is selective for mosquito Kir channels over several mammalian orthologs, with the exception of Kir2.1, and is not lethal to honey bees. Medicinal chemistry was used to develop an analog, termed VU730, which retains activity toward mosquito Kir1 but is not active against Kir2.1 or other mammalian Kir channels. Thus, VU041 and VU730 are promising chemical scaffolds for developing new classes of insecticides to combat insecticide-resistant mosquitoes and the transmission of mosquito-borne diseases, such as Zika virus, without harmful effects on humans and beneficial insects.

Highlights

The results of the present study provide compelling data that a small molecule inhibitor of mosquito Kir channels (VU041) offers a new active compound for the development of mosquitocides that overcome insecticide resistance and may be safe to humans and pollinators
The Akron strain of An. gambiae used in the present study carries multiple resistance mechanisms including 1) mutations in a voltage-gated Na+-channel that offers resistance to pyrethroids, 2) mutations in an AChE (MACE, ace-1R) that confers resistance to carbamates[30,31,32,33], and 3) metabolic resistance derived from increased biochemical levels of cytochrome P450 monoxygenases (CYP450s) and carboxylesterases[21]
A priori, one would not expect a mosquito strain with only target-site resistance in Na+ channels, such as the PR strain of Ae. aegypti used in this study, to exhibit resistance to a small molecule inhibitor of Kir channels

Summary

Introduction

Knocking down Kir[1] and Kir[2] mRNA expression in the heart and Malpighian (renal) tubules of Drosophila, respectively, inhibits the immune response against cardiotropic viruses[13] and transepithelial secretion of fluid and K+ 14. One of our goals is to identify Kir[1] inhibitors that can kill and/or incapacitate mosquitoes after topical application. We employed high-throughput screening to identify a Kir[1] inhibitor, termed VU041, which exhibits similar toxicity to adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively). VU041 represents a promising chemical scaffold for the development of a new generation of insecticides to control mosquitoes without harmful effects on humans and beneficial insects

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Conclusion