Azole Drug Import into the Pathogenic Fungus Aspergillus fumigatus
Azole Drug Import into the Pathogenic Fungus Aspergillus fumigatus
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DOI：
10.1128/aac.05003-14
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发表时间：
2015-06-01
影响因子：
4.9
通讯作者：
White, Theodore C.
中科院分区：
文献类型：
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作者：
Esquivel, Brooke D.;Smith, Adam R.;White, Theodore C.
真菌病原体烟曲霉会导致严重的疾病，当它侵入组织时往往会导致死亡，特别是在免疫功能低下的人身上。唑类药物是许多真菌感染最常用的处方药，作用于麦角固醇的生物合成途径。真菌中获得性唑类耐药性的一个常见机制是防止药物在细胞内积累到中毒水平。虽然药物外排是一种众所周知的耐药策略，但减少唑类进口将是另一种保持低细胞内唑水平的策略。最近，用[H-3]氟康唑分析了白色念珠菌和其他酵母菌对唑的摄取。药物进口缺陷可能是导致新生隐球菌、克鲁斯假丝酵母菌和酿酒酵母等病原真菌耐药的潜在机制。基于之前对白色念珠菌所做的工作，我们已经改进和开发了一种使用放射性标记的唑类药物来测量氮唑在烟曲霉菌中积累的方法。我们利用该方法研究了不同药物处理条件、不同形态的烟曲霉菌株和一株在甾醇吸收和生物合成途径方面存在缺陷的突变株在不同药物处理条件下对氮唑的吸收差异。我们得出结论，唑类药物是通过pH和ATP非依赖的促进扩散机制而不是被动扩散的方式特异性地选择和导入真菌细胞的。这种药物运输方法很可能在大多数真菌物种中都是保守的。
The fungal pathogen Aspergillus fumigatus causes serious illness and often death when it invades tissues, especially in immuno-compromised individuals. The azole class of drugs is the most commonly prescribed treatment for many fungal infections and acts on the ergosterol biosynthesis pathway. One common mechanism of acquired azole drug resistance in fungi is the prevention of drug accumulation to toxic levels in the cell. While drug efflux is a well-known resistance strategy, reduced azole import would be another strategy to maintain low intracellular azole levels. Recently, azole uptake in Candida albicans and other yeasts was analyzed using [H-3] fluconazole. Defective drug import was suggested to be a potential mechanism of drug resistance in several pathogenic fungi, including Cryptococcus neoformans, Candida krusei, and Saccharomyces cerevisiae. We have adapted and developed an assay to measure azole accumulation in A. fumigatus using radioactively labeled azole drugs, based on previous work done with C. albicans. We used this assay to study the differences in azole uptake in A. fumigatus isolates under a variety of drug treatment conditions, with different morphologies and with a select mutant strain with deficiencies in the sterol uptake and biosynthesis pathway. We conclude that azole drugs are specifically selected and imported into the fungal cell by a pH-and ATPindependent facilitated diffusion mechanism, not by passive diffusion. This method of drug transport is likely to be conserved across most fungal species.