Novel Approaches for Anthelmintic and Nematicide Discovery
Parasitic nematodes place an enormous burden on humanity. Nematodes infect over one quarter of the world’s population and cause billions of dollars in livestock and plant crop losses each year, threatening global food security. We rely heavily on the use of anthelmintic medicines and agrochemical nematicides to control these devastating parasitic nematode infections. The development of genetic resistance to anthelmintics and the phase-out of effective nematicides due to environmental toxicity and human safety concerns necessitates the discovery of new chemical controls for parasitic nematodes with novel targets and modes-of-action. The free-living nematode Caenorhabditis elegans has been an important model for identifying new lead chemical scaffolds with activity in parasitic nematodes and deciphering anthelmintic and nematicide mode-of-action. Here, I have used C. elegans as a model system, complemented by studies in parasitic nematodes, for the discovery and characterization of novel candidate anthelmintics and nematicides. I have taken two approaches towards achieving this goal. First, I have used small molecule screening and chemical genetic techniques in C. elegans to identify nematode kinases that hold potential as novel anthelmintic targets. I have complemented this work with in silico approaches to identify those kinases with potential for the design of nematode-selective inhibitors and identified those inhibitor scaffolds that could be modified to attain selectivity for the parasitic nematode ortholog of the target over that of the host. In my second study, I shift my focus to nematode parasites of plants. Here, I performed small molecule screens in both C. elegans and cultured parasitic species to identify compounds with broad spectrum activity across plant-parasitic nematodes. I used C. elegans to aid in the characterization of one promising selective nematicidal scaffold with a novel mode-of-action whereby the nematicide is bioactivated by cytochrome P450 enzymes within the worm. I ultimately show this mode-of-action to be conserved across parasitic nematode species. The investigations detailed herein have revealed a multitude of unexploited targets and small molecule scaffolds that may hold potential for development as sorely needed novel anthelmintics and nematicides to combat devastating parasitic nematode infections of humans, livestock, and plants.
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