The Magnitude of Candida albicans Stress-Induced Genome Instability Results from an Interaction Between Ploidy and Antifungal Drugs
The Magnitude of Candida albicans Stress-Induced Genome Instability Results from an Interaction Between Ploidy and Antifungal Drugs
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DOI：
10.1534/g3.119.400752
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发表时间：
2019-12-01
影响因子：
2.6
通讯作者：
Hickman, Meleah A.
中科院分区：
文献类型：
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作者：
Avramovska, Ognenka;Hickman, Meleah A.
生物体倍性和环境胁迫影响突变事件的速率和类型。机会致病真菌白色念珠菌是研究真核细胞倍性与药物致突变之间相互作用的临床相关模型。在这项研究中，我们比较了二倍体和四倍体C。白念珠菌暴露于两种不同类型的抗真菌药物;唑类和棘白菌素。我们测量了三种不同尺度的突变：点突变、杂合性丢失（洛）和暴露于氟康唑和卡泊芬净的细胞的总DNA含量。我们发现卡泊芬净诱导的突变率高于氟康唑，尽管这可能是应激相关细胞壁扰动的间接结果，而不是固有的遗传毒性。令人惊讶的是，我们发现抗真菌药物不成比例地增加了四倍体C。白色念珠菌与二倍体相比。两者合计，我们的研究结果表明，应力诱导的诱变结果倍性和抗真菌药物之间的相互作用的幅度。这些发现对于真菌病原体如何响应抗真菌药物应激而产生突变以及这些突变如何促进耐药性的出现具有临床和进化意义。
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.