The potential of pro‐insecticides for resistance management

Abstract

Pro‐insecticides have been a significant part of the insecticide market for decades. Bioactivation of such compounds is generally an enzyme‐controlled process, in which the target insect metabolizes the pro‐form into an active compound. This approach has several potential advantages, including improved bio‐kinetic properties and safety profiles of the pro‐insecticide relative to the active form. A less common advantage of pro‐insecticides is increased activity on metabolically resistant strains. Specific cases in which a pro‐insecticide demonstrates negative cross‐resistance (NCR) on a metabolically resistant strain due to increased bioactivation of the pro‐insecticide have been noted sporadically over the past 50+ years but have not been reviewed before. The purpose of this mini‐review is to catalog the cases in which a pro‐insecticide demonstrated improved activity on an insect strain resistant to a second insecticide via a metabolic mechanism. Cases are relatively rare, but where it does occur the mechanism of NCR is generally recognized as being due to the increased metabolic activity of the resistant strain. These observations can provide learnings with potential application for resistance management if the correct pro‐insecticide is selected for a resistant strain which is better able to bioactivate it. A better understanding of the bioactivation of pro‐insecticides by resistant insects could also aid in insecticide discovery, potentially leading to improved pro‐insecticide design. © 2021 Society of Chemical Industry

Efficacy of targeted indoor residual spraying with the pyrrole insecticide chlorfenapyr against pyrethroid-resistant Aedes aegypti

“…Some studies have demonstrated that detoxifying enzymes (P450s) in mosquitoes that are responsible for converting parent chlorfenapyr (CL303630) to its pro-insecticide metabolite (CL303268) can be inhibited with known inhibitors like PBO in measurable ways both in vivo and in vitro [ 29 , 43 , 44 ]. To less experienced researchers with this mode of action, the tendency to assume resistance rather than poor conversion (from parent to pro-insecticidal metabolite) requires consideration of laboratory or field-testing conditions which might interfere with chlorfenapyr’s mode of action [ 29 , 38 ] as influenced by numerous endogenous and exogenous elements [ 21 ]. Other studies point to induction routes which favor pre-exposures to neurotoxic chemistries (e.g., alpha-cypermethrin or others) which may actually enhance the conversion rates of the more toxic form of chlorfenapyr to mosquitoes as do more metabolically resistant mosquito strains (68,74).…”

“…The enzymatic transformation of parent chlorfenapyr (CL303630) to its pro-insecticidal metabolite (CL303268) can be slow and quite variable, but generally unidirectional once conversion has started [29]. The uncoupling of oxidative phosphorylation can be influenced by many exogenous and endogenous factors: temperature, cuticular penetrations, physical movement of challenged insects, host-seeking behaviors, PLOS NEGLECTED TROPICAL DISEASES blood-feeding status of mosquitoes, concentrations of chlorfenapyr challenged to insects from different substrates, degree of metabolic activity already within target pests and antagonisms by known metabolic inhibitors or competing resistant mechanisms (e.g., Glutathione S-Transferases or GSTs are not known to favor similar intoxication routes as cytochrome P450s) [21,29,37,38]. Ultimately, as chlorfenapyr is a physiological toxin, normal mosquito behaviors during their circadian rhythms will favor intoxication [19,20] and its evaluation in small cages may yield different (poorer) results compared to experimental houses.…”

Understanding the biological action of insecticides is the key to their continuous improvement

“…In his mini‐review, David asks the question of whether pro‐insecticides could have a natural advantage in the control of metabolically resistant insects due to their need for bioactivation 6 . Can pro‐insecticides use the increased metabolism of such insect strains against them by increasing the rate or extent of their metabolic bio‐activation?…”

Modern groups of insecticides: diamides and meta-diamides

“…Менее распространенное преимущество проинсектицидов -повышенная активность в отношении метаболически устойчивых популяций насекомых. Конкретные случаи, когда проинсектицид демонстрирует отрицательную перекрестную резистентность к метаболически устойчивой популяции из-за повышенной биоактивации проинсектицида, неоднократно отмечались за последние 50 лет (Salgado, David, 2017, Das, Mukherjee, 2018, David, 2021. Так, например, показана большая инсектицидность проинсектицида хлорфенапира (группа пирролов) для резистентных к пиретроидам комаров рода Culex (Yuan et al, 2015, Raghavendra et al, 2011 и мух-жигалок Haematobia irritans (Sheppard, Joyce 1998).…”