Fungal infections are often deadly in people with weakened immune systems—and they have become increasingly difficult to treat as the widespread use of antifungal drugs in medicine and agriculture has given rise to deadly drug-resistant strains.

One example is Cryptococcus neoformans, a fungus responsible for approximately 110,000 deaths annually from cryptococcal meningitis. Cryptococcal infections account for one in five AIDS-related deaths worldwide. Infections are most prevalent in sub-Saharan Africa, and fluconazole—an inexpensive and popular antifungal medication—is widely used there as treatment. However, fungal resistance is limiting the usefulness of the drug.

Rather than searching for new antifungals, researchers at the University of Guelph are pursuing a different strategy: making existing drugs effective again by reversing drug resistance.

“The drugs available now have been around for many years. We know how they function and how they respond within the human body—and many are widely accessible around the world,” says Dr. Jennifer Geddes-McAlister, Canada Research Chair in Proteomics of Fungal Disease in One Health and a professor in the University of Guelph’s Department of Molecular and Cellular Biology. “If we can make resistant fungal strains susceptible to the drugs again, we don’t have to come up with new drugs.”

Led by PhD student Michael Woods and M.Sc. graduate Arianne Bermas, Geddes-McAlister’s research team began by trying to understand what shifts inside fungal cells when they become resistant. By comparing resistant and non-resistant strains of C. neoformans, they identified six proteins of interest—including one known as ClpX, which plays several important roles in the fungus’s survival.

They then deleted ClpX or blocked it using a chemical called compound 334, and were able to successfully treat immune cells and mice infected with the altered fungus using fluconazole. The results of the study were published in July 2025 in Nature Communications.

A step closer to improved treatment

To explore compound 334’s potential as a treatment option for C. neoformans infections, Kerry Woolnough, a PhD student in bioinformatics who works with Geddes-McAlister, is using machine learning to tailor the compound to target ClpX in fungal cells without damaging human cells.

Beyond ClpX, Geddes-McAlister’s lab is also investigating four other potential protein candidates to reverse resistance to fluconazole in C. neoformans. If successful, these strategies could help make an inexpensive, widely available drug effective against fungal infections once again.

This article was adapted and published with permission from the University of Guelph.