C. elegans as a tool to discover new anthelmintics.

正如世界卫生组织（WHO）所指出的，“蠕虫感染给发展中国家的贫困人口带来了巨大的负担。”根据世界卫生组织的一份报告，全世界约有20亿人感染了线虫。线虫也是牲畜和植物的严重寄生虫，每年造成数十亿美元的作物损失和牲畜损失。伊维菌素是目前治疗线虫感染的首选药物。不幸的是，但并非出乎意料的是，对驱虫药的耐药性，特别是对伊维菌素的耐药性在世界范围内正在增长。这些关于伊维菌素耐药性的报告引起了人们的关注，许多组织呼吁开发治疗线虫感染的新药。***我们认为非感染性线虫秀丽隐杆线虫可以作为感染性线虫的有效替代品。秀丽隐杆线虫在实验室环境中易于处理，使其成为药物筛选和发现的理想选择。我们已经开发了一个高通量筛选系统，这将使我们能够探索潜在的杀线虫剂的化学景观的广泛采样。对线虫有效的化学物质可能很少，但如果我们能很容易地对许多化学物质取样，我们就有合理的机会发现新的杀线虫剂。在这种线虫中进行初级筛选的这种便捷性和速度应导致确定新的铅化学品，以开发作为杀线虫剂。***在一项针对3000种FDA批准的药物的初步研究中，我们发现了95%以上的已知杀线虫剂。虽然筛选仍在进行中，但我们已经确定了几种候选化合物。这些化合物以前都没有被证明对线虫有影响，事实上，对这些化合物的了解很少。从驱虫的角度来看，我们主要感兴趣的是进一步研究仅限于线虫的化合物。我们筛选的部分目的是寻找新的化学主干，因为它们可能最有可能影响尚未被开发的线虫的生化途径。我们相信这是开发新的驱虫药的一个很有前途的方法。***为了确定这些化合物的受影响途径和可能的耐药模式，我们将在诱变后选择耐药动物，然后确定受影响的位点。虽然这是一种历史悠久的方法，用于秀丽隐杆线虫鉴定与耐药有关的基因，但确定受影响位点的分子身份可能是一个瓶颈。我们已经开发了一种多重测序方案，可以很容易地识别耐药基因，并将其应用于该项目衍生的耐药菌株。长期目标将是与寄生虫学实验室合作，以确保这些药物在预期的目标生物上得到测试。如果成功，我们希望将这些化合物投入生产和测试，以帮助减轻全球范围内的驱虫病感染。**

As pointed out by the World Health Organization (WHO) "Helminth infections impose a great burden on poor populations in the developing world." According to a report by WHO, approximately 2 billion humans have nematode infections worldwide. Nematodes are also serious parasites of livestock and plants and cost billions of dollars a year in crop damage and loss of livestock. Ivermectin is currently the drug of choice to treat nematode infections. Unfortunately, but not unexpectedly, resistance to anthelmintic drugs in general and ivermectin in particular is growing worldwide. These reports of ivermectin resistance are cause for concern and have many organizations calling for the development of new drugs to treat nematode infections.***We believe the non-infectious nematode C. elegans can be used as an efficient surrogate for infectious nematodes. The ease of handling of C. elegans in a laboratory environment make it ideal for drug screening and discovery. We have developed a high throughput screening system that will allow us to explore a wide sampling of the chemical landscape for potential nematicides. Chemicals effective on nematodes may be rare, but if we can sample many chemicals easily we have a reasonable chance of identifying new nematicides. This ease and pace of primary screening in tis nematode should lead to identification of new lead chemicals to be developed as nematicides.***In a pilot study with a known set of 3,000 FDA approved drugs we identified over 95% of the known nematicides. While the screen is still in progress we already have identified several candidate compounds. None of these compounds have previously been shown to affect nematodes and indeed there is little known about any of the compounds. From the perspective of an anthelmintic we are primarily interested in doing further research on compounds with effects limited to nematodes. Part of our filtering was directed at looking for new chemical backbone's as they may be the most likely to affect biochemical pathways in the nematode that have not yet been exploited. We believe this is a promising approach for developing new anthelmintic drugs.***To identify affected pathways for these compounds and possible modes of resistance we will select for drug-resistant animals after mutagenesis and then identify the affected loci. While this has been a time-honored approach used in C. elegans to identify genes involved in drug resistance, determining the molecular identity of affected loci can be a bottleneck. We have developed a multiplex sequencing protocol to identify resistant genes quite easily and it will be applied to resistant strains derived from this project. Longer-term goals will be to work with parasitology labs to see that these drugs get tested on their intended target organisms. If successful we hope to move these compounds into manufacture and testing to help alleviate anthelmintic infections worldwide. **