A research team at McMaster University has discovered a new drug class that could someday lead to breakthrough treatments for dangerous fungal infections.
The new molecules, dubbed coniotins, were isolated from a plant-dwelling fungus called Coniochaeta hoffmannii – the samples of which were collected from the McMaster Biology Greenhouse, located on the university’s campus.
Detailed recently in the journal Nature Communications, the discovery responds to a critical need for new antifungal medicines.
“There is a huge, growing clinical need for new drugs that target fungal infections,” says Gerry Wright, a professor of biochemistry and biomedical sciences at McMaster and principal investigator on the new study. “Unlike antibiotics, of which there are dozens of different classes approved for use in clinics, there are really only three classes of antifungals on the market right now.”
The reason for such a limited arsenal, Wright says, is two-fold.
First, although disease-causing fungi are microscopic like bacteria and viruses, they’re actually more closely related to humans than they are to other microbes – “so things that kill fungi tend to kill us too,” he says. This makes finding antifungals that are safe for human consumption a real challenge.
And then there’s the historical lack of urgency. Wright says that most fungi cannot withstand our internal body temperature, and usually die off before they can cause serious infection. It’s why fungal infections typically occur on us instead of in us – think athlete’s foot, for example. Because our bodies can generally handle these pathogens naturally, Wright says there’s been little incentive for pharmaceutical companies to invest in antifungal R&D – until recently.
“Discovery remains a challenge today, but the level of urgency has changed dramatically over the past 15 years or so,” he says. “In 2009, a novel fungal pathogen called Candida auris emerged all over the world, and this fungus thrives at higher temperatures – and it can be extremely drug-resistant, too.”
C. auris is particularly problematic for individuals with compromised immune systems, like cancer patients undergoing chemotherapy. It can infect the lungs, the bloodstream, and the nervous system, and can be fatal. For these reasons, C. auris sits atop the World Health Organization’s list of priority fungal pathogens.
It’s a good thing then that the Wright Lab’s new molecule exhibits potent activity against C. auris.
Indeed, the research team showed that coniotins not only attack C. auris and several other fungal pathogens, but do so without harming human cells.
The fungal pathogen Candida albicans under attack by a new drug candidate discovered at McMaster University. The new drug compromises the fungal cell wall, evidenced by the collapsing and misshapen fungi, which are typically spherical. (Photo by Xufei Chen)
The new molecules function unlike any other antifungal on the market. Where most target proteins and membranes, coniotins instead bind to the fungal cell wall.
Wright, a member of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster, likens the cell wall to the candy coating on an M&M – a protective shell that provides structural integrity for what’s inside. Disturbing this structure, as coniotins do, fundamentally changes how well the organism can survive.
Xufei Chen.
Xufei Chen, a postdoctoral fellow in Wright’s lab and first-author on the new paper, identified the new drug class through a process called prefractionation, which allows scientists to tease specific molecules out from complex chemical mixtures.
“Since the golden age of antibiotic discovery, progress has slowed, due primarily to the frequent rediscovery of known compounds,” she says. “To address this, we implemented a prefractionation screening approach to target overlooked or masked metabolites. By integrating mass spectrometry, metabolomics, and computational analysis, I was able to discover this previously hidden molecule.”
Using this same process, Wright’s lab recently discovered a new class of antibiotics. They have also used prefractionation to identify several other new drug candidates, which remain under study.
“What’s really amazing is that we’ve only screened about five percent of the chemical library that we’ve built here at McMaster,” Wright says. “We have an immense, largely unexplored chemical space at our fingertips, and a cost-effective way to reduce the rediscovery of known compounds. Who knows what else is in there?”
Wright’s team is eager to move coniotins along the development pathway. The next steps, he says, include producing it at scale through fermentation, and formulating the new drug class so that it may eventually be suitable for intravenous (IV) delivery.