A testing cascade to identify repurposed insecticides for next-generation vector control tools: screening a panel of chemistries with novel modes of action against a malaria vector

Abstract

Background: With insecticide resistance in malaria vectors spreading in geographical range and intensity, there is a need for compounds with novel modes of action to maintain the successes achieved to date by long-lasting insecticidal nets and indoor residual sprays, used as part of an insecticide resistance management strategy. Screening existing registered pesticides, predominantly those developed for use in agriculture, may provide a more rapid and less logistically challenging route to identifying active ingredients of value to public health than screening and chemical synthesis programmes for novel compounds. Methods: Insecticides and acaricides from all IRAC classes, including those with unclassified modes of action, were assessed for inclusion in a laboratory bioassay testing cascade against adult female Anopheles gambiae mosquitoes. A longlist of representative candidate compounds was selected, excluding those with safety concerns, unsuitable physiochemical properties, and likely hurdles to registration for public health use. An initial screen using topical application eliminated compounds with insufficient intrinsic activity, and a tarsal contact assay identified those with activity at an appropriate concentration. Compounds of interest were ranked by relative potency using dose response assays and discriminating dose calculations. Results: Inclusion of an adjuvant enhanced the tarsal efficacy of several compounds, facilitating the promotion of chemistries with great potential, given suitable formulation, which would not progress based on activity of compound alone. Comparison of data between stages in the testing cascade suggest that a more streamlined approach, topical application to test for intrinsic activity and determining the discriminating dose to compare relative potency of compounds, may be sufficient to identify compounds with potential value for use in long lasting insecticidal nets and indoor residual spray products. Conclusions: Identified were 11 compounds of interest as vector control agents (in descending order of potency): clothianidin, spinetoram, metaflumizone, dinotefuran, indoxacarb, abamectin, sulfoxaflor, oxazosulfyl, triflumezopyrim, fenpyroximate, and tolfenpyrad.

Orthosteric muscarinic receptor activation by the insect repellent IR3535 opens new prospects in insecticide-based vector control

“…phosphorylation/dephosphorylation process) increases plasma membrane receptors and/or ion channels sensitivity to insecticides 18,23,50 . In this context, the use of repellent and insecticide co-formulated mixtures is a topic of great interest currently, particularly in the integrated vector management (IVM) 18,24,[51][52][53] . Here, we report the development of an innovative vector control strategy using IR3535.…”

Genome variation and population structure among 1142 mosquitoes of the African malaria vector species Anopheles gambiae and Anopheles coluzzii

“…Better surveillance can increase the impact and longevity of current mosquito control tools, but sustaining malaria control will also require the development of new tools (World Health Organization 2015). This includes repurposing existing insecticides from agriculture (Lees et al 2019;Oxborough et al 2019), developing entirely new insecticide classes, and developing tools that do not rely on insecticides, such as genetic modification of mosquito populations (Kyrou et al 2018). The research and development of new mosquito control tools has been greatly facilitated by the availability of high-quality open genomic data resources, including genome assemblies (Holt et al 2002;Sharakhova et al 2007), annotations (Giraldo-Calderón et al 2015), and, more recently, data on genetic variation in natural mosquito populations (The Anopheles gambiae 1000 Genomes Consortium 2017).…”

New insecticide screening platforms indicate that Mitochondrial Complex I inhibitors are susceptible to cross-resistance by mosquito P450s that metabolise pyrethroids

“…www.nature.com/scientificreports/ Analysis of transgenic lines overexpressing single P450 genes. Both fenpyroximate and tolfenpyrad have been shortlisted for further consideration in new vector control products 8 , and thus became the focus for in vivo studies. These were assayed against recently generated transgenic Gal4/UAS An.…”

“…Introducing insecticides with alternative modes of action to pyrethroids is critical to mitigate the current resistance issues in mosquito populations 2 . One of the ways to accelerate compounds through to utilisation in public health is through repurposing existing agricultural pesticides for use in appropriate formulations in mosquito control [7][8][9] . Indeed, a recent screen of 30,000 leads from agriculture chemistries against An.…”

“…Tolfenpyrad and fenpyroximate were further shortlisted for consideration as ingredients in new vector control products on the basis of favourable bioefficacy against pyrethroid susceptible An. gambiae 8 .…”