Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release

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 phylogen...

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Bibliographic Details
Published in:Communications biology 2022-08, Vol.5 (1), p.865-865, Article 865
Main Authors: Harrington, Sean, Knox, Jessica J., Burns, Andrew R., Choo, Ken-Loon, Au, Aaron, Kitner, Megan, Haeberli, Cecile, Pyche, Jacob, D’Amata, Cassandra, Kim, Yong-Hyun, Volpatti, Jonathan R., Guiliani, Maximillano, Snider, Jamie, Wong, Victoria, Palmeira, Bruna M., Redman, Elizabeth M., Vaidya, Aditya S., Gilleard, John S., Stagljar, Igor, Cutler, Sean R., Kulke, Daniel, Dowling, James J., Yip, Christopher M., Keiser, Jennifer, Zasada, Inga, Lautens, Mark, Roy, Peter J.
Format: Article
Language:English
Subjects:
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Acetylcholinesterase
Biology
Biomedical and Life Sciences
Convulsions
Crops
Drug resistance
Egg laying
Environmental impact
Life Sciences
Livestock
Nematicides
Nematodes
Neurotransmitter release
Paralysis
Parasites
Phylogeny
Plant protection
Worms
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Summary: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. A C. elegans -based screening approach identifies nementin as a nematode-selective nematicide that can be used synergistically with acetylcholinesterase inhibitors
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-03819-6