U of T Researchers Develop New Way to Target Plant-Parasitic Nematode Worms

A team led by University of Toronto researchers has discovered a new pesticide that selectively targets plant-parasitic nematode worms. In doing so, the group has uncovered a novel mechanism to selectively kill the nematodes.

Although the tiny worms are too small to be visible to the naked eye, they can destroy crops and have a major impact on the food supply.

The journal Nature published the findings today.

Traditional nematicides are effective against worms but also pose a risk to other animals and people. As a result, their use has been heavily restricted or banned in many counties, leaving farmers with few tools to protect their crops.

In the last 25 years, only seven 'next generation’ nematicides have been developed. One has already been banned in Europe, and the market release of another, which is formulated as a seed treatment, was postponed because people who used the product reported skin irritation. Hence, new pesticides with increased selectivity for nematodes are highly sought after.

“The nematodes crawl around in the soil. They feed on or infect plant roots and produce offspring that go on to infect and damage more crops,” said Andrew Burns, lead author on the paper and a research associate in the lab of Peter Roy, a professor in the Donnelly Centre for Cellular and Biomolecular Research at U of T’s Temerty Faculty of Medicine. “In addition to costing food growers a lot of money, this problem may threaten food security as the world’s population grows.”

The researchers found that a chemical compound called Selectivin (for selective imidazothiazole nematicide) kills nematode worms but has little impact on other organisms.

Selectivin works via a mechanism that involves a type of enzyme called cytochrome P450, which are present in nearly all living systems. Although the mechanism was known within other drug classes, the one Burns and Roy found is new within the nematicide chemical compound class.

When the researchers gave the Selectivin to the nematodes, the worms’ enzyme metabolized the chemical into a product that is toxic to the nematodes. This process — whereby an otherwise harmless substance becomes poisonous after it is metabolized — is called bioactivation.

The chemical compound’s selectivity is due, at least in part, to nematode-specific cytochrome P450s that are able to carry out the bioactivation reaction.

“The precursor molecule needs to be modified by this enzyme to become toxic. And that happens specifically in nematodes,” said Burns. “The nematicide is relatively benign on its own.”

Roy, who is also a professor of molecular genetics at U of T and holds the Tier 1 Canada Research Chair in Chemical Genetics, said that while the novel nematicide is an exciting discovery, so is the new understanding of its mechanism of action, which could be applied to agricultural pests or vectors of human disease.

“I think this could open the eyes of industry movers and shakers to the value of identifying selective nematicides and pesticides they might not have considered before, and that could potentially lead to new compounds that will be both safe and selective,” said Roy. “Further, this work highlights the value of using C. elegans for early-stage drug discovery.”

C. elegans is a free-living nematode worm species that is also a common model organism in studies of animal development and human disease. Burns was inspired to explore Selectivin following his earlier work screening chemicals to explore their effects on C. elegans.

When he noticed many chemicals killed the worms, Burns wanted to know how that was happening and whether that information could be leveraged to help fight parasitic nematode infections in animals and plants.

While Burns was learning more about the various chemicals, he noticed structural similarities between Selectivin and levamisole, an anthelmintic drug used to treat nematode infections in people and livestock.

Despite their commonalities, Burns also noted slight structural differences between Selectivin and levamisole. This realization led him to theorize that the two might have different mechanisms of action.

With the help of their collaborators, the team tested Selectivin’s effect on other organisms and confirmed that it was only bioactive in the nematodes and did no harm to other model systems like yeast, bacteria, fruit flies and zebrafish.

This research was supported by grants from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, David Dime Family Catalyst Fund and the Alberta Innovates Technology Fund.