Using a catalogue of mutations to predict resistance to antifungal drugs

To help clinicians choose the right drugs to treat fungal infections, researchers have classified the protective effects of some 4000 mutations in Candida albicans, a pathogenic fungus that is the most common cause of fungal infections.

There are currently only four types of antifungal drugs, and fungal pathogens’ resistance to these drugs makes treatment more complex. A research team at Université Laval has identified the mutations in Candida albicans that make it resistant to six azole antifungal drugs that are in widespread clinical use. This team’s study, published in the journal Nature Microbiology, classifies these mutations and their resistance to the various azole agents in a catalogue that clinicians can use for guidance in choosing a course of treatment.

The study’s first author is Camille Bédard, a doctoral student in Laval’s Faculty of Science and Engineering who is a 2024 Vanier Scholar and is being supervised by Professor Christian Landry. Bédard underscores the need to find a suitable antifungal drug rapidly, without any trial and error: “Among immunodepressed patients, the mortality rate for C. albicans infections can be as high as 70%. If clinicians know which mutation of this fungus they are dealing with and which drugs it is resistant to, they can consult this catalogue to determine the appropriate treatment.”

Most resistance mutations (88%) provide cross-resistance to several azole medications. Because all of the azoles that the researchers tested had the same mechanism of action, they had expected to observe this cross-resistance, but not in such a high proportion of the mutations. As Bédard explains, “Azoles act by binding with a protein that is key for the growth of the pathogen, thereby inhibiting it. When a resistance mutation arises, the drug can no longer bind to the protein and thus becomes ineffective.” Because azole molecules vary somewhat from one another, she had not expected the mutations to provide such broad resistance.

Bédard is concerned with the issue of cross-resistance to azoles because this family of antifungals is also used in agriculture. As she cautions, “Some pathogens present in the environment can enter the human body—for example, humans may inhale the spores of Aspergillus fumigatus, a soil fungus. In immunodepressed individuals, this can cause infections. If the pathogen has had previous contact with an agricultural azole in the soil, it may have developed a resistance that also protects it from medical azoles.”

In a future study, Bédard wants to evaluate the rate of cross-resistance between agricultural and medical azoles for A. fumigatus and other fungi of the same type.

Rather than choosing mutations that seem to be of interest, the research team looks at all possible mutations, which increases the catalogue’s predictive power. Says Bédard, “We can generate and study mutations that have not yet been observed in nature but might emerge in future. Thus, even if a mutation is observed for the first time in a clinical setting, it will appear in the catalogue and the clinician can know whether or not it provides resistance.”

To study the 4000 potential mutations, the researchers use a model yeast (brewer’s yeast) and modify it genetically to produce the same protein as the C. albicans pathogen that is targeted by the azole drug. They then test resistance by placing all of the “mutants” in the presence of each antifungal. Those that survive will be classified as resistant.

The team now wants to determine whether the resistant mutations identified for C. albicans will be the same in other pathogenic fungi. As Bédard puts it, “Could we use this same catalogue for other fungi, or would we need a separate catalogue for each pathogen?”

This study was published in the journal Nature Microbiology. The other authors from Université Laval are Isabelle Gagnon-Arsenault, Jonathan Boisvert, Samuel Plante, Alexandre K. Dubé, Alicia Pageau, Anna Fijarczyk and Christian R. Landry. The other co-authors of this study are Jehoshua Sharma, Laetitia Maroc and Rebecca S. Shapiro, all from the University of Guelph.

This article has been adapted, translated and published with the permission of Université Laval.

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