Knockdown resistance (kdr) to pyrethroids
Pyrethroid insecticides are synthetic derivatives of pyrethrum, a natural insecticide from Chrysanthemum species. Their insecticidal activity results from the disruption of the function of voltage-gated sodium channels. Pyrethroid insecticides are widely used to control many medically and agriculturally important arthropod pests and, due to their low mammalian toxicity, are the major class of insecticides that are approved for global use in insecticide-treated bednets for malaria control due to their low mammalian toxicity. The intensive use of pyrethroids, however, has led to the development of resistance to these compounds in many insect populations.
One of the most important mechanisms of pyrethroid resistance, known as knockdown resistance (kdr), is caused by mutations in the sodium channel gene which reduced sensitivity of the target-site (sodium channel) to pyrethroids. Using a combination of molecular genetic, electrophysiological, pharmacological, structural biology, and computational modeling approaches, we made major contributions to the elucidation of the molecular mechanism of kdr resistance in various arthropods species. In collaboration with Prof. Boris Zhorov (McMaster Univ.), we predicted dual pyrethroid-binding sites on the mosquito sodium channel that explain not only much of pyrethroid resistance found in mosquito populations worldwide but also the notable selectivity of pyrethroids between insects vs. mammals. Currently, we collaborate with the laboratory of Prof. Nieng Yan (Princeton Univ) to determine cryo-EM structures of sodium channels in complex with pyrethroids, as a guide to conduct a comprehensive series of mutational, electrophysiological, and computational modeling analyses of sodium channel-pyrethroid interactions. The ultimate goal is to map out the complete pyrethroid-binding pockets on the sodium channel and reveal the molecular basis of pyrethroid action on the sodium channel.