Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
Sean Harrington, Jessica Knox, Andrew R. Burns, Ken‐Loon Choo, Aaron Au, Megan Kitner, Cécile Haeberli, Jacob Pyche, Cassandra D’Amata, Yong‐Hyun Kim, Jonathan Volpatti, Maximillano Guiliani, Jamie Snider, Victoria Wong, Bruna M. Palmeira, Elizabeth Redman, Aditya S. Vaidya, John S. Gilleard, Igor Štagljar, Sean R. Cutler, Daniel Kulke, James J. Dowling, Christopher M. Yip, Jennifer Keiser, Inga A. Zasada, Mark Lautens, Peter J. Roy
Abstract
Nematode parasites of humans, livestock and crops dramatically impact human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogenetic selectivity. Here, we exploit multiple motor outputs of the model nematode C. elegans towards nematicide discovery. This work yielded multiple compounds that selectively kill and/or immobilize diverse nematode parasites. We focus on one compound that induces violent convulsions and paralysis that we call nementin. We find that nementin stimulates neuronal dense core vesicle release, which in turn enhances cholinergic signaling. Consequently, nementin synergistically enhances the potency of widely-used non-selective acetylcholinesterase (AChE) inhibitors, but in a nematode-selective manner. Nementin therefore has the potential to reduce the environmental impact of toxic AChE inhibitors that are used to control nematode infections and infestations.