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

中文翻译：

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黑腹果蝇的胰岛素信号通路：揭示 DDT 抗性的“阿喀琉斯之踵”的联系

杀虫剂抗性是农业和病媒控制中的一个持续挑战。在这里，我们展示了一种减轻阻力的新策略。我们使用基因组学工具来定位与能量相关的基本途径，并确定了潜在的抗性“阿喀琉斯之踵”，这是一种抗性相关蛋白，在被抑制后会导致抗性表型的大量丧失。具体而言，我们比较了 DDT 易感 (91-C) 和抗性 (91-R) 黑腹果蝇 (Drosophila) 菌株中胰岛素/胰岛素样生长因子信号 (IIS) 通路基因的基因表达谱和结构变异。与 91-C 相比，91-R 中总共有 8 个和 7 个 IIS 转录本分别上调和下调。在 91-C 和 91-R 之间共观察到 114 个非同义突变，其中 51 个。8% 是固定的。在差异表达的转录物中，磷酸烯醇丙酮酸羧激酶 (PEPCK) 在 91-R 中下调，编码的氨基酸变化数量最多，促使我们进行 PEPCK 抑制剂-农药暴露生物测定。PEPCK 抑制剂硫酸肼导致 DDT 抗性表型 (91-R) 降低 161 至 218 倍，91-C 敏感性增加 4 至 5 倍以上。第二种靶蛋白，糖原合酶激酶 3β (GSK3β-PO)，在 91-C 和 91-R 之间有一个氨基酸差异，相应的转录本也在 91-R 中下调。GSK3β-PO 抑制剂氯化锂同样降低了阻力，但比硫酸肼对 PEPCK 的降低程度要小。我们证明了 IIS 基因在 DDT 抗性中的潜在作用以及“