Fungal infections claim millions of lives every year, yet treatment options have failed to keep pace with the growing danger. Scientists at McMaster University now report a discovery that could shift that balance. They have identified a molecule called butyrolactol A that targets a highly dangerous disease-causing fungus known as Cryptococcus neoformans.

Cryptococcus infections can be life-threatening. The fungus often triggers pneumonia-like illness and is especially hazardous for people with weakened immune systems, including cancer patients and individuals living with HIV. It is also known for resisting many available drugs. Other fungal threats show similar behavior, including Candida auris and Aspergillus fumigatus. Like Cryptococcus, both have been designated priority pathogens by the World Health Organization.

Despite the severity of these infections, doctors are limited to just three major antifungal treatment options.

Limited Treatments and Toxic Side Effects

The most effective antifungal drugs belong to a class called amphotericin. However, these drugs are notorious for harming patients as well as pathogens. Gerry Wright, a professor in McMaster’s Department of Biochemistry and Biomedical Sciences, jokes that amphotericin is often referred to as "amphoterrible" because of its severe toxic effects on humans.

"Fungal cells are a lot like human cells, so the drugs that hurt them tend to hurt us too," he says. "That’s why there are so few options available to patients."

The remaining two antifungal drug classes, azoles and echinocandins, are far less effective, particularly against Cryptococcus. According to Wright, azoles only slow fungal growth instead of killing the organism. Echinocandins have become useless against Cryptococcus and several other fungi due to widespread resistance.

Turning to Helper Molecules for a New Strategy

With few approved drugs, little progress in the antifungal pipeline, and rising resistance, researchers are now focusing on a different approach using compounds known as adjuvants.

"Adjuvants are helper molecules that don’t actually kill pathogens like drugs do, but instead make them extremely susceptible to existing medicine," explains Wright, a member of the Michael G. DeGroote Institute for Infectious Disease Research (IIDR).

To find an adjuvant that could make Cryptococcus more vulnerable to treatment, Wright’s team screened thousands of compounds from McMaster’s extensive chemical library.

Rediscovering an Overlooked Molecule

The researchers quickly identified a promising candidate. Butyrolactol A is a molecule produced by certain Streptomyces bacteria that had been known for decades but largely ignored. When paired with echinocandin drugs, the compound enabled those drugs to kill fungi they could not eliminate on their own.

At first, the team did not understand how the molecule worked and nearly dismissed it.

"This molecule was first discovered in the early 1990s, and nobody has ever really looked at it since," Wright says. "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.’"

Persistence Pays Off

Wright says the project continued thanks to the persistence of postdoctoral fellow Xuefei Chen.

"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."

Years of detailed investigation followed, which Wright describes as "painstaking sleuthing and detective work." That effort ultimately revealed how butyrolactol A functions.

How the Molecule Disarms Deadly Fungi

Chen discovered that butyrolactol A blocks a protein complex that is essential for Cryptococcus survival. Wright describes the effect vividly. "When it’s jammed, all hell breaks loose." Once this critical system is disrupted, the fungus becomes fully exposed to drugs it previously resisted.

Further experiments showed the molecule has similar effects on Candida auris. The team worked alongside researchers in the lab of McMaster Professor Brian Coombes, also a member of the IIDR. These results suggest the discovery could have broad clinical potential beyond a single pathogen.

More Than a Decade in the Making

Wright says the findings, recently published in the journal Cell, represent more than ten years of research.

"That first screen that put butyrolactol A on our radar took place in 2014," he notes. "More than eleven 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 breakthrough marks the second antifungal compound and the third new antimicrobial discovered by Wright’s lab within the past year.