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

• DOI: 10.1038/s42003-022-03819-6
• Publication Date: 2022-08-24T17:03:02Z
• Authors: Sean Harrington; Jessica J. Knox; Andrew R. Burns; Ken-Loon Choo; Aaron Au; Megan Kitner; Cecile Haeberli; Jacob Pyche; Cassandra D’Amata; Yong-Hyun Kim; Jonathan R. Volpatti; Maximillano Guiliani; Jamie Snider; Victoria Wong; Bruna M. Palmeira; Elizabeth M. Redman; Aditya S. Vaidya; John S. Gilleard; Igor Stagljar; Sean R. Cutler; Daniel Kulke; James J. Dowling; Christopher M. Yip; Jennifer Keiser; Inga Zasada; Mark Lautens; Peter J. Roy
• Keywords: 0301 basic medicine; Neurotransmitter Agents; Nematoda; QH301-705.5; Antinematodal Agents; Article; 3. Good health; 03 medical and health sciences; Acetylcholinesterase; Animals; Humans; Biology (General); Caenorhabditis elegans; CAENORHABDITIS-ELEGANS ; NIPPOSTRONGYLUS-BRASILIENSIS ; ACETYLCHOLINESTERASE ; G(Q)ALPHA ; HELMINTHS ; GENETICS ; PATHWAY ; CHANNEL ; VESICLE ; CAPS; Phylogeny

Abstract Nematode parasites of humans, livestock and crops dramatically impact human health welfare. Alarmingly, parasitic nematodes animals have rapidly evolved resistance to anthelmintic drugs, traditional nematicides that protect are facing increasing restrictions because poor phylogenetic selectivity. Here, we exploit multiple motor outputs the model nematode C. elegans towards nematicide discovery. This work yielded compounds selectively kill and/or immobilize diverse parasites. We focus on one compound induces violent convulsions paralysis call nementin. find nementin stimulates neuronal dense core vesicle release, which in turn enhances cholinergic signaling. Consequently, synergistically potency widely-used non-selective acetylcholinesterase (AChE) inhibitors, but a nematode-selective manner. Nementin therefore has potential reduce environmental toxic AChE inhibitors used control infections infestations.