Abstract
Author SummaryFungal infections are a particularly challenging problem in medicine due to the small number of effective antifungal drugs available. Fluconazole, the most commonly prescribed antifungal, prevents cells from growing but does not kill them, giving the fungal population a window of opportunity to become drug resistant. Candida albicans is the most prevalent fungal pathogen, and many fluconazole-resistant strains of this microbe have been isolated in the clinic. Fluconazole-resistant isolates often contain an abnormal number of chromosomes (a state called aneuploidy), and the additional copies of drug resistance genes on those chromosomes enable the cells to circumvent the drug. How Candida cells acquire abnormal chromosome numbers is a very important medical question—is aneuploidy merely passively selected for, or is it actively induced by the drug treatment? In this study, we found that fluconazole and other related azole antifungals induce abnormal cell cycle progression in which mother and daughter cells fail to separate after chromosome segregation. Following a further growth cycle, these cells form an unusual cell type that we have termed “trimeras”—three-lobed cells with two nuclei. The aberrant chromosome segregation dynamics in trimeras produce progeny with double the normal number of chromosomes. Unequal chromosome segregation in these progeny leads to an increase in the prevalence of aneuploidy in the population. We postulate that the increase in aneuploidy greatly increases the odds of developing drug resistance.
Highlights
Fungal pathogens have a profound effect on human health, causing millions of deaths worldwide [1]
How Candida cells acquire abnormal chromosome numbers is a very important medical question—is aneuploidy merely passively selected for, or is it actively induced by the drug treatment? In this study, we found that fluconazole and other related azole antifungals induce abnormal cell cycle progression in which mother and daughter cells fail to separate after chromosome segregation
Some aneuploidies provide a selective advantage in the presence of FLC [13], it is unknown if the rate of aneuploid formation is increased or if rare aneuploid cells within the population are actively selected in response to FLC exposure
Summary
Fungal pathogens have a profound effect on human health, causing millions of deaths worldwide [1]. Candida albicans is among the most prevalent fungal human pathogens [1] and was long thought to be an obligate diploid (2N DNA content). True meiotic divisions have not been detected in C. albicans, tetraploids (4N DNA content) form in vitro, via mating between diploids [2,3,4], and undergo ‘‘concerted chromosome loss’’ (CChrL), a nonmeiotic reduction in chromosome number [5]. The existence of semistable, nondiploid C. albicans cell types highlights the flexibility of the C. albicans genome It raises important questions about how nondiploid isolates, aneuploids, arise and are maintained especially in light of the fitness cost associated with aneuploidy in the model yeast Saccharomyces cerevisiae under optimal growth conditions [8,9,10,11]
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