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

Authors: HARRINGTON, S - University Of Toronto; KNOX, J - University Of Toronto; BURNS, A - University Of Toronto; CHOO, K - University Of Toronto; AU, A - University Of Toronto; Kitner, Megan; HAEBERLI, C - Swiss Tropical Institute(STI); PYCHE, J - University Of Toronto; D'AMATA, C - University Of Toronto; KIM, Y - University Of Toronto; VOLPATTI, J - Hospital For Sick Children (SICKKIDS); GUILIANI, M - University Of Toronto; SNIDER, J - University Of Toronto; WONG, V - University Of Toronto; PALMEIRA, B - University Of Calgary; REDMAN, E - University Of Calgary; VAIDYA, A - University Of California; GILLEARD, J - University Of Calgary; STAGLJAR, I - University Of Toronto; CUTLER, S - University Of California; KULKE, D - University Of Toronto; DOWLING, J - Hospital For Sick Children (SICKKIDS); YIP, C - University Of Toronto; KEISER, J - Swiss Tropical Institute(STI); Zasada, Inga; LAUTENS, M - University Of Toronto; ROY, P - University Of Toronto

Submitted to: Communications Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/8/2022
Publication Date: 8/24/2022
Citation: Harrington, S., Knox, J., Burns, A., Choo, K., Au, A., Kitner, M.L., Haeberli, C., Pyche, J., D'Amata, C., Kim, Y., Volpatti, J., Guiliani, M., Snider, J., Wong, V., Palmeira, B., Redman, E., Vaidya, A., Gilleard, J., Stagljar, I., Cutler, S., Kulke, D., Dowling, J., Yip, C., Keiser, J., Zasada, I.A., Lautens, M., Roy, P. 2022. Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release. Communications Biology. 5. Article 865. https://doi.org/10.1038/s42003-022-03819-6.
DOI: https://doi.org/10.1038/s42003-022-03819-6

Interpretive Summary: Both human- and plant-parasitic nematodes, roundworms, are of economic significance globally due their impacts on human health and crop productivity, respectively. New chemical compounds are needed to replace traditional chemicals that are more targeted against nematodes. Research was conducted to discover new nematicides. A new nematicide, Nementin, was identified that may improve the control of these important parasites.

Technical Abstract: Nematode parasites of humans, livestock and crops pose a significant burden on 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 a lack phylogenetic-selectivity. Here, we present a C. elegans-based motor-centric discovery pipeline that yielded four new and selective nematicidal molecules. We show that one of these, which we call Nementin, immobilizes larvae of multiple nematode parasites in vitro. We used C. elegans to show that Nementin induces convulsions by agonizing dense core vesicle release, which in turn agonizes cholinergic signalling as a secondary effect. Consequently, Nementin can synergistically enhance the anthelmintic potency of restricted organophosphate and carbamate acetylcholinesterase inhibitors. Hence, Nementin is a novel candidate anthelmintic that may also improve the selectivity of broad-acting pesticides. anthelmintic that may also improve the selectivity of broad-acting pesticides.