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Knockdown Resistance (kdr) to Pyrethroids

Pyrethroids are a large class of structurally diverse, synthetic analogues of natural pyrethrins from the flower extracts of the chrysanthemum, Tanacetum cinerariaefolium. They are widely used to control many arthropod pests and disease vectors because they are broad-spectrum, fast-acting, highly effective and relatively safe for humans. Currently, pyrethroids are the only class of insecticides used in insecticide-treated bed nets, which represent one of the most powerful control measures in the fight against malaria-carrying mosquitoes. Unfortunately, intensive use of pyrethroids has led to the development of pyrethroid-resistant insects, which have become a global problem in managing many agricultural pests and disease vectors. A major mechanism of pyrethroid resistance known as knockdown resistance (kdr), is caused by reduced neuronal sensitivity to pyrethroids. The kdr mechanism has been documented worldwide in all major arthropod pests and disease vectors.

Knockdown resistance (kdr) to DDT and pyrethroids.

Knockdown resistance (kdr) to DDT and pyrethroids.

Pyrethroids act on the voltage-gated sodium channels in the nervous system. In the past decade, our group and several other research teams have taken a combination of genetic, molecular, electrophysiological and pharmacological approaches to elucidate the kdr mechanism in multiple arthropod pests. These studies uncovered a collection of mutations in voltage-gated sodium channels that confer pyrethroid resistance by reducing pyrethroid binding and/or via altering sodium channel gating to counteract the action of pyrethroids.

Kdr mutations in the sodium channel.
Kdr mutations in the sodium channel.

The ultimate goals of our research are: (1) to map out the pyrethroid binding sites on the sodium channel and (2) to define the interaction of sodium channels with structurally diverse pyrethroids at the molecular and atomic levels. The voltage-gated sodium channel consists of four homologous domains (I to IV). Computer modeling of the pyrethroid receptor site in the house fly sodium channel using crystal structures of potassium channels showed a pyrethroid receptor site at the interface between domain II and domain III (O’Reilly et al., 2006). In collaboration with Prof. Boris Zhorov (McMaster University, Canada), we recently discovered a second pyrethroid receptor site on a mosquito sodium channel from Aedes aegypti at the interface between domain I and domain II (Du et al., 2013). Collectively these results suggest that binding of pyrethroids to two receptor sites in a four-domain sodium channel is necessary to efficiently lock sodium channels in the open state and, thereby, exert the highly insecticidal action. Pyrethroids modify various gating processes including activation, inactivation and deactivation of sodium channels. Understanding the molecular mechanism of pyrethroid binding and action will advance our understanding of the structure-function relationship of sodium channels.

Pyrethroid dual-receptor sites.

Pyrethroid dual-receptor sites.