依布硒啉通过调节真菌细胞中的谷胱甘肽 (GSH) 和活性氧 (ROS) 产生来发挥抗真菌活性。
Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells.
机构信息
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA.
Faculty in Libraries, Purdue University, West Lafayette, IN 47906, USA.
出版信息
Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):3002-3010. doi: 10.1016/j.bbagen.2016.09.029. Epub 2016 Oct 3.
BACKGROUND
Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remain unclear.
METHODS
The antifungal effect of ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of ebselen. Ebselen's antifungal activity in vivo was investigated in a Caenorhabditis elegans animal model.
RESULTS
Ebselen exhibits potent antifungal activity against both Candida spp. and Cryptococcus spp., at concentrations ranging from 0.5 to 2μg/ml. Ebselen rapidly eradicates a high fungal inoculum within 2h of treatment. Investigation of the drug's antifungal mechanism of action indicates that ebselen depletes intracellular glutathione (GSH) levels, leading to increased production of reactive oxygen species (ROS), and thereby disturbs the redox homeostasis in fungal cells. Examination of ebselen's in vivo antifungal activity in two Caenorhabditis elegans models of infection demonstrate that ebselen is superior to conventional antifungal drugs (fluconazole, flucytosine and amphotericin) in reducing Candida and Cryptococcus fungal load.
CONCLUSION
Ebselen possesses potent antifungal activity against clinically relevant isolates of both Candida and Cryptococcus by regulating GSH and ROS production. The potent in vivo antifungal activity of ebselen supports further investigation for repurposing it for use as an antifungal agent.
GENERAL SIGNIFICANCE
The present study shows that ebselen targets glutathione and also support that glutathione as a potential target for antifungal drug development.
背景
依布硒啉是一种有机硒化合物，也是一种临床安全的分子，已被报道具有很强的抗真菌活性，但它的抗真菌作用机制和体内抗真菌活性尚不清楚。
方法
测试了依布硒啉对白色念珠菌、光滑念珠菌、热带念珠菌、近平滑念珠菌、新型隐球菌和格特隐球菌临床分离株的抗真菌作用。采用化学基因组学谱分析和生化分析来确定依布硒啉的抗真菌靶标。在秀丽隐杆线虫动物模型中研究了依布硒啉的体内抗真菌活性。
结果
依布硒啉对白色念珠菌和隐球菌均具有很强的抗真菌活性，浓度范围为 0.5 至 2μg/ml。依布硒啉在治疗 2 小时内即可迅速消除高真菌接种物。对药物抗真菌作用机制的研究表明，依布硒啉耗尽细胞内谷胱甘肽（GSH）水平，导致活性氧（ROS）产生增加，从而扰乱真菌细胞的氧化还原稳态。在两种秀丽隐杆线虫感染模型中研究依布硒啉的体内抗真菌活性表明，依布硒啉在降低白色念珠菌和隐球菌真菌负荷方面优于传统抗真菌药物（氟康唑、氟胞嘧啶和两性霉素）。
结论
依布硒啉通过调节 GSH 和 ROS 产生对临床上相关的白色念珠菌和隐球菌分离株具有很强的抗真菌活性。依布硒啉在体内的强大抗真菌活性支持进一步研究将其重新用于抗真菌药物。
一般意义
本研究表明，依布硒啉的靶标是谷胱甘肽，也支持谷胱甘肽作为抗真菌药物开发的潜在靶标。
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