Knockdown resistance in mosquito vectors: Molecular mechanisms, global spread, and future directions for sustainable...

Pyrethroid insecticides remain central to malaria and dengue vector control programmes. However, their long-term effectiveness is increasingly threatened by knockdown resistance (kdr). kdr arises from mutations in the voltage-gated sodium channel (VGSC) gene, particularly within the IIS6 and IIIS6 domains, which reduce insecticide binding while preserving normal neuronal function. Key mutations include L1014 substitutions in Anopheles species and V1016 and F1534 variants in Aedes species. These mutations have evolved independently across multiple endemic regions under sustained insecticide pressure. This review integrates molecular, functional, evolutionary, and operational evidence to examine how kdr is reshaping contemporary vector control. It summarizes global trends in allele frequency changes, findings from electrophysiological and genome-editing studies confirming causal mechanisms, and multilocus analyses demonstrating progressive resistance intensification. Particular emphasis is placed on the interaction between target-site mutations and metabolic detoxification pathways, which together amplify resistance intensity and complicate genotype-phenotype interpretation. The review further discusses surveillance strategies, evidence-based thresholds for insecticide switching, the role of synergist-enhanced formulations, alternative chemical classes, and integrated vector management approaches. Emerging genetic technologies, including CRISPR-based editing and gene drive systems, are evaluated within realistic regulatory and ecological frameworks. By linking molecular mechanisms with field performance and programme-level decision-making, this synthesis positions kdr not merely as a mutation class but as a dynamic indicator of selective pressure and intervention sustainability in mosquito-borne disease control.