Global distribution and impact of knockdown resistance mutations in Aedes aegypti on pyrethroid resistance

Abstract The ongoing fight against mosquito-borne diseases such as dengue, Zika, and chikungunya is increasingly challenged by Aedes aegypti resistance to pyrethroid insecticides. This resistance is primarily driven by knockdown resistance (kdr) mutations in the voltage-gated sodium channel ( Vgsc ) gene, which have been identified in different regions with significant variability in their prevalence and impact. Managing Ae. aegypti populations in the face of this resistance require in-depth understanding of the global distribution of kdr mutations and their relationship to insecticide use patterns. This narrative review identifies a diverse landscape of kdr mutations, with common mutations such as V1016I, F1534C, and L982W, the latter of which has recently gained attention as an important mutation contributing to resistance in various regions, often co-occurring with other mutations and leading to enhanced resistance phenotypes. Additional mutations including V410L, G923V, S989P, I1011M/V, and D1763Y further complicate the resistance profile, indicating a dynamic evolution of resistance in response to pyrethroid use. This review also highlights significant gaps in current research, particularly in understanding the interaction between kdr mutations and other resistance mechanisms, such as metabolic detoxification by enzymes like cytochrome P450s, glutathione S -transferases (GST), and esterases, and the need for more standardized methodologies for data collection and reporting. The widespread use of pyrethroids has significantly contributed to the global spread of kdr mutations in Ae. aegypti , thereby challenging the efficacy of the current chemical vector control strategies. Despite these challenges, pyrethroids remain essential for mosquito control owing to their proven efficacy, rapid action, and versatility. However, the rising levels of resistance highlight the need for an integrated approach to vector management that combines chemical, biological, and community-based strategies. Future research should address these gaps through longitudinal studies and the development of new insecticides and resistance management strategies to address the growing threat of insecticide resistance in Ae. aegypti and protect public health. Graphical Abstract