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Abstract：
Antifungal resistance and antifungal tolerance are two distinct terms that describe different cellular responses to drugs. Antifungal resistance describes the ability of a fungus to grow above the minimal inhibitory concentration (MIC) of a drug. Antifungal tolerance describes the ability of drug susceptible strains to grow slowly at inhibitory drug concentrations. Recent studies indicate antifungal resistance and tolerance have distinct evolutionary trajectories. Superficial candidiasis bothers millions of people yearly. Miconazole has been used for topical treatment of yeast infections for over 40 years. Yet, fungal resistance to miconazole remains relatively low. Here we found different clinical isolates of Candida albicans had different profile of tolerance to miconazole, and the tolerance was modulated by physiological factors including temperature and medium composition. Exposure of non-tolerant strains with different genetic backgrounds to miconazole mainly induced development of tolerance, not resistance, and the tolerance was mainly due to whole chromosomal or segmental amplification of chromosome R. The efflux gene CDR1 was required for maintenance of tolerance in wild type strains but not required for gain of aneuploidy-mediated tolerance. Heat shock protein Hsp90 and calcineurin were essential for maintenance as well as gain of tolerance. Our study indicates development of aneuploidy-mediated tolerance, not resistance, is the predominant mechanism of rapid adaptation to miconazole in C. albicans, and the clinical relevance of tolerance deserves further investigations.
摘要：
抗真菌耐药性和抗真菌耐受性是描述对药物的不同细胞反应的两个不同术语。抗真菌抗性描述了真菌在药物的最小抑制浓度(MIC)以上生长的能力。抗真菌耐受性描述了药物敏感菌株在抑制药物浓度下缓慢生长的能力。最近的研究表明抗真菌抗性和耐受性具有不同的进化轨迹。浅表念珠菌病每年困扰数百万人。咪康唑已经用于酵母菌感染的局部治疗超过40年。然而，真菌对咪康唑的耐药性仍然相对较低。在这里，我们发现不同的白色念珠菌临床分离株对咪康唑的耐受性不同，耐受性受温度和培养基成分等生理因素的调节。不同遗传背景的非耐受性菌株暴露于咪康唑主要诱导耐受性的发展，不是抵抗,耐受性主要是由于R染色体的全染色体或分段扩增。外排基因CDR1是维持野生型菌株耐受性所必需的，但不是获得非整倍体介导的耐受性所必需的。热休克蛋白Hsp90和钙调磷酸酶对于维持和获得耐受性至关重要。我们的研究表明非整倍体介导的耐受性的发展，不是抵抗,是白色念珠菌快速适应咪康唑的主要机制，耐受性的临床意义值得进一步研究。
