Exploiting Caenorhabditis elegans as a Discovery Platform to Identify Nematode Parasiticides that Act Through Neuromuscular Disruption

Nematodes that parasitize humans, non-human animals and plants are an underappreciated burden to human health, food security and economic development. The compounds that rid animals and plants of parasitic nematode infections, termed nematode parasiticides, are tremendously important for human development. The emergence of genetic resistance and warranted restriction on the use of toxic parasiticides beckon the development of a new generation of effective compounds to combat nematode parasites. Most nematode parasiticides developed to date act through neuromuscular disruption. this is an effective strategy as several behaviours that are essential for maintaining a state of parasitism including feeding, reproduction, and attachment to host tissues rely on neuromuscular function. The non-parasitic nematode Caenorhabditis elegans has emerged as a powerful biological study model. The neuromuscular biology of C. elegans is well conserved with nematode parasites of plants and animals. Here, I describe my efforts towards identifying and characterizing novel parasiticidal compounds using Caenorhabditis elegans as a discovery model. I first exploited C. elegans egg-laying behaviour to identify small-molecules that disrupt C. elegans neuromuscular function. I identified two scaffolds that disrupt C. elegans neuromuscular function that also demonstrate potent activity against nematode parasites of animals and plants. The first scaffold that I describe, wact-55, disrupts nematode motor behaviours by eliciting the release of neurotransmitter containing vesicles through yet uncovered mechanisms. Wact-55 demonstrates a strong synergistic interaction with inhibitors of acetylcholinesterase, an established class of nematode parasiticides. The second scaffold that I describe, wact-45, is an inhibitor of the vesicular acetylcholine transporter that flaccidly paralyzed nematodes. Wact-45 synergistically kills C. elegans with the most commercially successful nematode parasiticide ivermectin. Thus, I have identified two novel parasiticide scaffolds that may prove useful for combatting nematode parasites that plague humans.

Department dc:contributor.department

Pharmacology

Year dc:date.issued

2022

Author dc:creator

• Harrington, Sean Patrick

Advisor dc:contributor.advisor

• Roy, Peter J

• anthelmintic
• antiparasitic
• caenorhabditis elegans
• egg laying
• nematicide
• parasiticide

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/136539

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/136539