New family of compounds shows promise in treating parasitic worms

An international team of researchers led by the University of Toronto has discovered a family of natural compounds with the potential to create new and more effective treatments for parasitic worms. These compounds block a unique metabolic process that worms use to survive in the human intestine.

Parasitic soil-borne worms are wreaking havoc on developing countries in the tropics. Infection with these parasites results in malaise, weakness, malnutrition and other debilitating symptoms and can cause birth defects and impair growth in children.

Parasitic soil-borne worms infect more than one billion people worldwide, mostly in low-income communities in developing countries that lack comprehensive health care and sanitation systems. Parasites are becoming less susceptible to the few available anthelmintic drugs, so the search for new compounds is urgently required.

Taylor Davie, first author of the study and a graduate student at the Donnelly Center for Cellular and Biomolecular Research at the University of Toronto

The study was published today in the journal Nature Communications.

Many species of parasitic worms spend most of their life cycle inside a human host. To adapt to the conditions of the intestinal environment, especially the lack of oxygen, the parasite switches to a type of metabolism that depends on a molecule called rhodoquinone (RQ).

The parasite can survive inside its human host for many months using RQ-dependent metabolism.

The research team decided to target the parasitic worm's adaptive metabolic process because RQ is only present in the parasite's system; the person does not produce or use RQ. Therefore, compounds that can regulate the production or activity of this molecule selectively kill the parasite without harming the human host.

Researchers screened natural compounds isolated from plants, fungi and bacteria using the model organism C. Elegans. Although not a parasite, this worm also depends on RQ for metabolism when oxygen is not available.

"This is the first time we have been able to look for drugs that specifically target the unusual metabolism of these parasites," said Andrew Fraser, the study's principal investigator and professor of molecular genetics at the Donnelly Center and Temerty School of Medicine.

"This screen was made possible by recent successes by our group and others in using C. Elegans to study RQ-dependent metabolism, as well as our collaboration with RIKEN, one of Japan's largest research agencies. We scanned their outstanding collection of 25,000 natural compounds, which led to the discovery of a family of benzimidazole compounds that kill worms depending on this type of metabolism."

Researchers propose using a multi-dose regimen using a newly discovered family of compounds to treat parasitic worms. Although single dose treatment is more convenient for mass drug treatment programs, a longer treatment program will be more effective in killing parasites.

“We are very pleased with the results of the research for which we used our library,” said Hiroyuki Osada, professor of pharmacy at Shizuoka University and director of the chemical biology group at the RIKEN Center for Sustainable Resources.

"The study demonstrates the power of the screening approach, allowing researchers in this case to screen a very large number of molecules within a concentrated collection of natural products. Screens are very efficient, which is key to addressing urgent research questions of global importance like this."

Next steps for the research team include refining the new class of inhibitors through additional in vivo tests with parasitic worms, which will be conducted by the Kaiser laboratory at the University of Basel in Switzerland, and continuing the search for compounds that inhibit RQ.

"This study is just the beginning," Fraser said. "We have found several other very potent compounds that affect this metabolism, including for the first time a compound that blocks the worms' ability to produce RQ. We hope our screens will help develop drugs to treat major pathogens around the world."

This research was supported by the Institutes of Health Canada and the European Molecular Biology Organization.