C. elegans as a tool to discover new anthelmintics.

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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. **