kdr mutations differentially impact mosquito sodium channel sensitivity to structurally diverse pyrethroids

Pyrethroids are a major class of synthetic insecticides that target insect voltage-gated sodium (Na_v) channels, disrupting neuronal signaling. Over time, structural modifications have generated a wide diversity of pyrethroid compounds with varying potency and insecticidal activity. Knockdown resistance (kdr) arises from mutations that reduce Na_v channel sensitivity, thereby diminishing pyrethroid effectiveness. While most kdr mutations confer broad resistance, our recent work showed that V253F and M918T selectively reduced channel sensitivity to deltamethrin but not to transfluthrin, indicating structure-specific effects. To further investigate, we evaluated another linker mutation, L199F, located in the IS2–S3 and co-occurring with F1534C in field populations of Aedes aegypti in Asia. Functional characterization in Xenopus oocytes revealed that L199F selectively decreased AaNav1-1 channel sensitivity to bioallethrin but not to deltamethrin or transfluthrin. In contrast, the double mutant F1534C+L199F reduced sensitivity to both bioallethrin and transfluthrin, but not deltamethrin. V253F and M918T did not affect bioallethrin, consistent with previous findings for transfluthrin. These findings highlight that the structural diversity of pyrethroids can drive distinct resistance genotypes, emphasizing the need to integrate insecticide chemistry into understanding molecular interactions at the target sites and resistance monitoring for vector control strategies.