The Magnitude of Candida albicans Stress-Induced Genome Instability Results from an Interaction Between Ploidy and Antifungal Drugs

Organismal ploidy and environmental stress impact the rates and types of mutational events. The opportunistic fungal pathogen Candida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and drug-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploid C. albicans following exposure to two different classes of antifungal drugs; azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-of-heterozygosity (LOH), and total DNA content for cells exposed to fluconazole and caspofungin. We found that caspofungin induced higher mutation rates than fluconazole, although this is likely an indirect consequence of stress-associated cell wall perturbations, rather than an inherent genotoxicity. Surprisingly, we found that antifungal drugs disproportionately elevated genome and ploidy instability in tetraploid C. albicans compared to diploids. Taken together, our results suggest that the magnitude of stress-induced mutagenesis results from an interaction between ploidy and antifungal drugs. These findings have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress and how these mutations may facilitate the emergence of drug resistance.