After 11 years of research, scientists at McMaster University have identified a molecule called butyrolactol A that weakens deadly fungi, making them vulnerable to existing treatments. This discovery targets pathogens like Cryptococcus neoformans, which pose severe risks to immunocompromised individuals. The finding could revive outdated antifungal drugs amid rising resistance.
Fungal infections kill millions annually, but options for treatment remain scarce and increasingly ineffective due to drug resistance. Researchers at McMaster University report a breakthrough with butyrolactol A, a compound produced by Streptomyces bacteria and overlooked since its discovery in the early 1990s. This molecule acts as an adjuvant, not directly killing fungi but sabotaging their internal systems to expose them to drugs they once resisted.
The primary target is Cryptococcus neoformans, a fungus that causes pneumonia-like illnesses and is particularly dangerous for people with weakened immune systems, such as those with HIV or cancer. It joins other WHO-designated priority pathogens like Candida auris and Aspergillus fumigatus, which also evade many therapies. Current antifungal classes are limited: amphotericin, known for its toxicity—Gerry Wright, a professor in McMaster's Department of Biochemistry and Biomedical Sciences, calls it "amphoterrible"—along with azoles that merely slow growth and echinocandins rendered useless by resistance.
"Fungal cells are a lot like human cells, so the drugs that hurt them tend to hurt us too," Wright explains. "That's why there are so few options available to patients."
The team's screening of thousands of compounds from McMaster's library in 2014 pinpointed butyrolactol A. Postdoctoral fellow Xuefei Chen persisted despite initial doubts. "Early on, this molecule's activity appeared to be quite good," Chen says. "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."
Detailed studies revealed that butyrolactol A blocks a vital protein complex in Cryptococcus, causing chaos within the fungus. "When it's jammed, all hell breaks loose," Wright describes. Experiments also showed efficacy against Candida auris, in collaboration with Professor Brian Coombes' lab. Published in Cell in 2025, this marks the second antifungal compound from Wright's lab in the past year, offering hope for broader applications.
