Inhibition of the pentose phosphate pathway to interfere with metabolic mechanisms of insecticide resistance: Evaluation of a potential pyrethroid synergist

Resistance to pyrethroid based insecticides has facilitated the rapid spread of Aedes

aegypti throughout California. Resistance in California is mediated by both target site mutations and metabolic mechanisms of resistance. For our study, we collected wild pyrethroid resistant F2 Ae. aegypti from the Central Valley of California and pyrethroid susceptible Rock mosquitoes. We apportioned 12 pools of 10 adult female Ae. aegypti organized by population and submitted them to the West Coast Metabolomics Center for high-throughput metabolomic analysis. This technique offers a snapshot of the insects’ metabolomes, revealing different levels of activity and demands on metabolic pathways. We identified elevated levels of metabolites associated with the pentose phosphate pathway (PPP). We then hypothesized resistant Ae. aegypti may have increased demands for NADPH, an product of the PPP, and that inhibition with this pathway could interfere with metabolic resistance mechanisms. We identified a compound, Polydatin, which acts as an inhibitor of glucose-6-phosphate dehydrogenase, a rate limiting step in the PPP. We evaluated the ability of polydatin to act as a pyrethroid synergist, and found polydatin significantly decreased time to knock-down in CDC bottle bioassays with permethrin, and increased 24 mortality following permethrin exposure. We are evaluating Polydatin’s viability to act as a novel pyrethroid synergist.