Mechanism of action of natural and biorational insecticides

Abstract

<p>Conventional insecticides constitute some of our greatest tools to control insect pests but have become increasingly undesirable due to adverse environmental effects, human health complications, and the growing prevalence of insecticide resistance development. Natural products such as terpenes and biorational compounds synthesized from natural chemicals have risen as a promising avenue for insecticide development. Several biorational pyrones have proven to be highly effective insecticides, rapidly killing or paralyzing Dipteran pests in laboratory studies, but the mechanism of action (MoA) behind this lethality is unknown. This thesis proposes that a new class of biorational pyrones synthesized from pogostone, a molecule extracted from patchouli oil, act as neurotoxicant insecticides. Two insecticide neural targets were selected to explore this hypothesis: acetylcholinesterase (AChE), a nervous system enzyme responsible for breaking down the acetylcholine neurotransmitter, and the nicotinic acetylcholine receptor (nAChR), which triggers nerve signals upon binding of the endogenous ligand, acetylcholine. This thesis expands on previous terpene (MoA) research, specifically studying the ability of several terpenes to inhibit adult mosquito AChE. I determined that AChE inhibition is not an important MoA for terpene bioactivity in mosquitoes. Several biorational pyrones were found capable of inhibiting adult Aedes aegypti mosquito AChE, but results indicated that this may not be the primary MoA for pyrones. Biorational pyrones were subsequently screened for their ability to modulate binding of radiolabeled [14C]-nicotine to nAChR in house fly head membrane preparations. Radiolabeled nicotine acts as an agonist of the insect nAChR, thus disruption of [14C]-nicotine binding indicates that a chemical may be interfering with this integral central nervous system signaling pathway. Pogostone and several biorational pyrones were capable of significantly inhibiting [14C]-nicotine binding to the insect nAChR on a similar scale as unlabeled nicotine, but the results did not necessarily prove this to be an important MoA for biorational pyrones. In total, these studies shed some light on how biorational pyrones operate within the neural physiology of two Dipteran species, but leaves many open questions and further avenues of study.</p>