New treatment for drug-resistant fungal infections

Fungal infections kill millions of people each year, and modern medicine is struggling to keep up. But researchers have identified a molecule that may help turn the tide — butyrolactol A, a chemical compound that targets a deadly, disease-causing fungi called Cryptococcus neoformans. 

Infections caused by Cryptococcus are extremely dangerous. The pathogen, which can cause pneuomia-like symptoms, is notoriously drug-resistant, and it often preys on 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, though, doctors have only three treatment options for fungal infections.  

The gold standard is a drug class called amphotericin but has major toxic side-effects on humans.  

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

The other two antifungal drug classes that are available — azoles and echinocandins — are much less effective treatment options, especially against Cryptococcus. The author 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 something called “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,” explains the author. 

Looking for adjuvants that might better sensitize Cryptococcus to existing antifungal drugs, the lab screened vast chemical collection for candidate molecules.  

Quickly, the team found a hit: butyrolactol A, a known-but-previously understudied molecule produced by certain Streptomyces bacteria. The researchers found that the molecule could synergize with echinocandin drugs to kill fungi that the drugs alone could not.

But they had no idea how it worked — and almost didn’t bother to find out.

“This molecule was first discovered in the early 1990s, and nobody has ever really looked at it since,” the author 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.’”

“Early on, this molecule’s activity appeared to be quite good,” says the first author. “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 the author calls “painstaking sleuthing and detective work” , the research team revealed exactly how the adjuvant worked.

The author 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,” the senior author says. This disturbance renders the fungus completely vulnerable to the drugs that it once resisted.

Mechanistically, butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1-butyrolactol A complex reveals that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency.

The research team has since shown that butyrolactol A also functions similarly in Candida auris, which gives it broad clinical potential.  

https://www.cell.com/cell/abstract/S0092-8674(25)01371-6