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

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.