Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans.
Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans.
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DOI：
10.1093/jac/dki089
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发表时间：
2005-05
期刊：
影响因子：
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通讯作者：
H. Sigle;S. Thewes;M. Niewerth;H. Korting;M. Schäfer-Korting;B. Hube
中科院分区：
文献类型：
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作者：
H. Sigle;S. Thewes;M. Niewerth;H. Korting;M. Schäfer-Korting;B. Hube
环吡酮是一种羟基吡啶酮类局部抗真菌药，其作用机制尚不清楚。为了阐明环吡酮的作用机制，我们分析了暴露于这种抗真菌剂后的多态性酵母菌白色念珠菌的生长、细胞完整性、生化特性、活力和转录谱。方法采用多种生物化学方法鉴定抗真菌活性的关键因素，并鉴定药物暴露细胞中活性发生变化的蛋白质。全基因组转录谱用于鉴定响应于药物的细胞效应而上调的基因。结果环吡酮对C.白念珠菌、酵母菌和菌丝细胞呈剂量依赖性。（i）通过向生长培养基中添加铁离子或代谢抑制剂2-脱氧-D-葡萄糖，（ii）在缺乏葡萄糖的培养基中，以及（iii）对于用过氧化氢或甲萘醌预孵育的细胞[其引起参与活性氧（ROS）解毒的蛋白质的诱导]，这种效应降低。相比之下，在低氧条件下预培养的细胞（其具有降低的参与ROS解毒的蛋白质活性）对环吡酮更敏感。用环吡酮治疗不会直接引起细胞膜损伤，也不会改变细胞内ATP水平。最后，药物处理细胞的转录谱模式非常类似于铁限制条件。结论代谢活性、氧可及性和铁水平是环吡酮胺作用方式的关键参数。
OBJECTIVES Ciclopirox is a topical antifungal agent of the hydroxypyridone class whose mode of action is poorly understood. In order to elucidate the mechanism of action of ciclopirox, we analysed the growth, cellular integrity, biochemical properties, viability and transcriptional profile of the polymorphic yeast Candida albicans following exposure to this antifungal agent. METHODS Multiple biochemical assays served to identify factors that were critical for antifungal activity and to identify proteins whose activities changed in drug-exposed cells. Genome-wide transcriptional profiling was used to identify genes that were up-regulated in response to the cellular effects of the drug. RESULTS Ciclopirox inhibited growth of C. albicans yeast and hyphal cells in a dose-dependent manner. This effect was reduced (i) by the addition of iron ions or the metabolic inhibitor 2-deoxy-D-glucose to growth media, (ii) in media that lacked glucose, and (iii) for cells that were pre-incubated with hydrogen peroxide or menadione [which caused induction of proteins involved in detoxification of reactive oxygen species (ROS)]. In contrast, cells pre-cultured under poor oxygen conditions (which had decreased activity of proteins involved in ROS detoxification) were more susceptible to ciclopirox. Treatment with ciclopirox did not directly cause cell membrane damage and did not change intracellular levels of ATP. Finally, the transcriptional profiling pattern of drug-treated cells strongly resembled iron-limited conditions. CONCLUSIONS These data indicate that metabolic activity, oxygen accessibility and iron levels are critical parameters in the mode of action of ciclopirox olamine.