The insulin signaling pathway in Drosophila melanogaster: A nexus revealing an “Achilles' heel” in DDT resistance

Insecticide resistance is an ongoing challenge in agriculture and disease vector control. Here, we demonstrate a novel strategy to attenuate resistance. We used genomics tools target fundamental energy-associated pathways identified potential “Achilles' heel” for resistance, resistance-associated protein that, upon inhibition, results substantial loss the phenotype. Specifically, compared gene expression profiles structural variations of insulin/insulin-like growth factor signaling (IIS) pathway genes DDT-susceptible (91-C) -resistant (91-R) Drosophila melanogaster (Drosophila) strains. A total eight seven IIS transcripts were up- down-regulated, respectively, 91-R 91-C. 114 nonsynonymous mutations observed between 91-C 91-R, which 51.8% fixed. Among differentially expressed transcripts, phosphoenolpyruvate carboxykinase (PEPCK), down-regulated encoded greatest number amino acid changes, prompting us perform PEPCK inhibitor–pesticide exposure bioassays. The inhibitor PEPCK, hydrazine sulfate, resulted 161- 218-fold decrease DDT phenotype more than 4- 5-fold increase susceptibility second protein, Glycogen synthase kinase 3β (GSK3β-PO), had one difference corresponding transcript was also 91-R. GSK3β-PO inhibitor, lithium chloride, likewise reduced but lesser extent did sulfate PEPCK. role discovery against pesticide this pathway.