Fungal infections kill millions of people each year, and modern medicine is struggling to keep up. But researchers at McMaster University in Canada have identified a molecule that may help turn the tide — butyrolactol A, a chemical compound that targets the deadly, disease-causing fungus Cryptococcus neoformans.
Cryptococcus infections are extremely dangerous. The pathogen, which can cause pneumonia-like symptoms, is notoriously drug-resistant, and often affects people with weakened immune systems, like cancer patients or those living with HIV. And the same can be said about other fungal pathogens, like Candida auris or Aspergillus fumigatus — both of which, like Cryptococcus, have been declared priority pathogens by the World Health Organization.
Despite the threat, doctors have only three treatment options for fungal infections.
The gold standard is the drug class amphotericin — though Gerry Wright, a professor in McMaster’s Department of Biochemistry and Biomedical Sciences, jokes that it’s often called “amphoterrible,” because of the major toxic side-effects that it has on humans.
“Fungal cells are a lot like human cells, so the drugs that hurt them tend to hurt us too. That’s why there are so few options available to patients,” he said.
The other two antifungal drug classes available — azoles and echinocandins — are much less effective treatment options, especially against Cryptococcus. Wright says azoles merely stop fungi from growing rather than outright killing them, while Cryptococcus and other fungi have become totally resistant to echinocandins, rendering them completely ineffective.
So, with a stagnant antifungal drug pipeline, a limited arsenal of approved medicines, and rising rates of drug resistance, scientists are now betting on adjuvants as a solution to the growing health threat.
“Adjuvants are helper molecules that don’t actually kill pathogens like drugs do, but instead make them extremely susceptible to existing medicine,” said Wright, a member of the Michael G. DeGroote Institute for Infectious Disease Research (IIDR).
Looking for adjuvants that might better sensitize Cryptococcus to existing antifungal drugs, Wright’s lab screened McMaster’s vast chemical collection for candidate molecules.
Quickly, his team found a hit: butyrolactol A, a known-but-previously-understudied molecule produced by certain Streptomyces bacteria. The researchers found the molecule could synergize with echinocandin drugs to kill fungi that the drugs alone could not.
“This molecule was first discovered in the early 1990s, and nobody has ever really looked at it since,” Wright said.
“So, when it showed up in our screens, my first instinct was to walk away from it. I thought, ‘it’s a known compound, it kind of looks like amphotericin, it’s just another toxic molecule — not worth our time.’”
But he credits the determination of postdoctoral fellow Xuefei Chen for changing his mind.
“Early on, this molecule’s activity appeared to be quite good,” says Chen, who works in Wright’s lab.
“I felt that if there was even a small chance that it could revive an entire class of antifungal medicine, we had to explore it.”
After years of what Wright calls “painstaking sleuthing and detective work” led by Chen, the research team revealed exactly how the adjuvant worked.
Chen discovered that butyrolactol A acts as a plug that clogs up an important protein complex that’s “mission critical” for Cryptococcus.
“When it’s jammed, all hell breaks loose,” Wright said.
The disturbance renders the fungus completely vulnerable to the drugs that it once resisted.
Working with researchers in the laboratory of McMaster professor Brian Coombes, also a member of the IIDR, the research team has since shown that butyrolactol A also functions similarly in C. auris, giving it broad clinical potential.
Wright said the findings, published recently in the journal Cell, are more than a decade in the making.
“That first screen that put butyrolactol A on our radar took place in 2014. More than 11 years later, thanks almost entirely to Chen, we have identified a legitimate drug candidate and an entirely new target to attack with other new drugs.”
The discovery is the second antifungal compound and third new antimicrobial found by Wright’s lab in the past year.
Jim Cornall is editor of Deeptech Digest and publisher at Ayr Coastal Media. He is an award-winning writer, editor, photographer, broadcaster, designer and author. Contact Jim here.
