Fungal infections, which are often deadly in people with weakened immune systems, have become increasingly difficult to treat. That is because the widespread use of antifungal drugs in medicine and agriculture is driving resistance to the limited arsenal of available medications.
Rather than searching for new antifungals, researchers from the University of Guelph are pursuing a different strategy: making existing drugs effective again by reversing resistance.
"The drugs available now have been around for many years. We know how they function, how they respond within the human body, and many are widely accessible around the world," says Dr. Jennifer Geddes-McAlister, professor in the Department of Molecular and Cellular Biology and Canada Research Chair in Proteomics of Fungal Disease in One Health.
"If we can make resistant fungal strains susceptible to the drugs again, we don't have to come up with new ones."
Restoring sensitivity to fluconazole
In a study recently published in Nature Communications, Geddes-McAlister's team led by PhD student Michael Woods and M.Sc. grad Arianne Bermas found that blocking or removing a particular protein in a resistant strain of Cryptococcus neoformans effectively reversed its resistance to fluconazole, an inexpensive and widely used antifungal medication.
C. neoformans is an especially dangerous fungus, responsible for cryptococcal meningitis, a brain infection that kills approximately 110,000 people every year. Cryptococcal infections account for one in five AIDS-related deaths worldwide. Infections are most prevalent in sub-Saharan Africa and fluconazole is widely used there as treatment.
In the lab, researchers compared drug-resistant and drug-responsive strains of the C. neoformans fungus to better understand what shifted inside fungal cells when they become resistant.
They identified six proteins of interest, including ClpX, which plays several important roles in the fungus's survival. After either deleting clpX or blocking it using a chemical called Compound 334, immune cells and mice infected with the altered fungus were successfully treated with fluconazole again.
A step closer to improved treatment
With further research, Compound 334 has potential as a future treatment option.
Kerry Woolnough, a PhD student in bioinformatics working with Geddes-McAlister, has begun this work using machine learning to tailor the compound to target ClpX in fungal cells, without damaging human cells.
Besides ClpX, Geddes-McAlister's lab is 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.
