Unravelling the novel mode of action of the spinosyn insecticides: A 25 year review.

Since their registration more than 25 years ago, the spinosyns have become a significant insect management tool in farmers' battles to protect crop quality and yield. Spinosad (Qalcova™ active) and spinetoram (Jemvelva™ active)1, the two members of the Insecticide Resistance Action Committee (IRAC) Group 5 nicotinic acetylcholine receptor (nAChR) allosteric modulators Site I, class of insecticides, have proven highly effective at controlling chewing insect pests on over 250 different crops. Their importance as an integral rotation partner in insect pest management programs has stimulated a large body of research into their mode of action (MoA) and mechanisms of resistance. This review aims to synthesize recent advances in our understanding of the unique MoA of spinosyn insecticides and interactions with their key target, the α6 subunit from the insect nAChR gene family. Significant developments towards a reliable functional expression system for insect nAChR subtypes that respond to IRAC Group 4 insecticides (nAChR competitive modulators, such as neonicotinoids) have been made and we will contrast this with recent progress on heterologous expression of spinosyn responsive nAChR subtype combinations. We review the impact gene-editing technology has had, particularly its use to systematically interrogate individual subunits of the Drosophila melanogaster nAChR gene family and broader use in pest insects. Insights from the consolidation of these findings provide a valuable resource for resistance monitoring and resistance modeling that should help guide sustainable use of spinosyn insecticides in insect pest management programs. Future areas of research that could help refine our understanding of the novel MoA of spinosyn insecticides are also highlighted.