Analyses of aphid sodium channels and prediction of pesticide interactions

在可预见的未来，全世界的粮食作物生产很可能依赖于使用农用化学品来控制病虫害。据估计，如果不防治虫害，当前农业产量将损失25%-75%(因作物而异)，尽管努力开发非化学方法，但虫害的控制在很大程度上仍然是通过使用杀虫剂来实现的。然而，许多杀虫剂的使用受到昆虫进化抗性机制的严重威胁，这种机制使这些化学物质无效。这种抵抗对英国和世界各地的农业都构成了严重威胁。抗药性可能是由于昆虫对杀虫剂解毒能力的增强，或者是杀虫剂与之相互作用的蛋白质发生了变化。两种杀虫剂，滴滴涕和合成拟除虫菊酯(后者目前约占世界杀虫剂市场的17%)作用于昆虫神经细胞膜上的钠通道蛋白。这些通道的正确功能对于神经冲动的正常传递至关重要，这一过程会被杀虫剂的结合迅速扰乱，导致瘫痪和最终死亡。一些害虫种群已经进化出钠通道蛋白的修饰，这种修饰抑制了杀虫剂的结合，导致昆虫产生抗药性。以前在我们的实验室(在Rothamsted Research和其他地方)所做的工作已经识别了在抗药性昆虫中改变的钠通道上的特定位点，为DDT和拟除虫菊酯结合位点的位置提供了线索。随着蚜虫全基因组序列的出现，将有可能研究一组重要农业害虫的钠离子通道，这些害虫的耐药性普遍存在。因此，当前项目的主要目标是利用计算机生成的模型和实验室生成的突变通道的测试相结合的方式来确定蚜虫通道上的杀虫剂结合位点。预计这最终将使设计出对迄今具有抗药性的昆虫具有高杀虫活性的新型分子成为可能。

For the foreseeable future the worldwide production of food crops is likely to be dependant on the use of agrochemicals to control pests and diseases. It is estimated that 25-75% (varies between crops) of current agricultural output would be lost without pest control and despite efforts to develop non-chemical methods the control of insect pests is still largely achieved by the use of insecticides. However, the use of many groups of insecticides is severely threatened by the ability of insects to evolve resistance mechanisms that render the chemicals ineffective. Such resistance poses a serious threat to agriculture both in the UK and worldwide. Resistance may result from either an increase in the ability of the insect to detoxify the insecticide or by changes in the proteins with which the insecticide interacts. Two types of insecticide, DDT and the synthetic pyrethroids (the latter currently account for around 17% of the world insecticide market), act on sodium channel proteins found in insect nerve cell membranes. The correct functioning of these channels is essential for normal transmission of nerve impulses and this process is rapidly disrupted by binding of the insecticides, leading to paralysis and eventual death. Some insect pest populations have evolved modifications of the sodium channel protein which inhibit the binding of the insecticide and result in the insect developing resistance. Previous work done in our laboratories (at Rothamsted Research and elsewhere) has led to the identification of specific sites on the sodium channel that are changed in resistant insects providing clues on the location of the DDT and pyrethroid binding sites. With the advent of the full genome sequence for an aphid, it will be possible to study the sodium channel in a group of important agricultural pests, where resistance is widespread. Thus the key aim of the current project is to define insecticide binding sites on the aphid channel using a combination of computer-generated models and testing of laboratory-generated mutant channels. It is anticipated that this will eventually enable the design of novel molecules with high insecticidal activity on hitherto resistant insects.