Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells.
Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells.
复制标题
DOI：
10.1016/j.bbagen.2016.09.029
复制
发表时间：
2017-01
影响因子：
3
通讯作者：
Seleem, Mohamed N.
中科院分区：
文献类型：
--
作者：
Thangamani, Shankar;Eldesouky, Hassan E.;Mohammad, Haroon;Pascuzzi, Pete E.;Avramova, Larisa;Hazbun, Tony R.;Seleem, Mohamed N.
依布硒啉是一种有机硒化合物，临床安全，具有较强的抗真菌活性，但其抗真菌作用机制和体内抗真菌活性尚不清楚。测定了依布硒啉对白色念珠菌、假丝酵母菌、白念珠菌的抑菌作用。光叶C. tropicalis、热带假丝酵母C.近平滑病、新型隐球菌和隐球菌C.格特氏临床分离株。采用化学基因组分析和生化分析来鉴定依布硒啉的抗真菌作用靶点。在秀丽隐杆线虫动物模型中研究Ebselen的体内抗真菌活性。依布硒啉对念珠菌属和假丝酵母属均具有强效抗真菌活性。和隐球菌属，浓度范围为0.5 - 2 μg/ml。Ebselen在治疗后两小时内迅速根除高真菌接种物。对药物抗真菌作用机制的研究表明，依布硒啉消耗细胞内谷胱甘肽（GSH）水平，导致活性氧（ROS）产生增加，从而扰乱真菌细胞中的氧化还原稳态。在两种秀丽隐杆线虫感染模型中检查依布硒啉的体内抗真菌活性表明，依布硒啉在减少念珠菌和隐球菌真菌负荷方面上级常规抗真菌药物（氟康唑、氟胞嘧啶和阿替霉素）。依布硒啉通过调节GSH和ROS的产生，对念珠菌和隐球菌的临床相关分离株具有有效的抗真菌活性。依布硒啉在体内的有效抗真菌活性支持进一步研究将其重新用作抗真菌剂。本研究表明，依布硒啉靶向谷胱甘肽，也支持谷胱甘肽作为抗真菌药物开发的潜在靶点。
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 remains unclear. 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. Ebselen exhibits potent antifungal activity against both Candida spp. and Cryptococcus spp, at concentrations ranging from 0.5 – 2 μg/ml. Ebselen rapidly eradicates a high fungal inoculum within two hours 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. 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. The present study shows that ebselen targets glutathione and also support that glutathione as a potential target for antifungal drug development.
登录
查看更多内容
影响因子：
14
作者：
Cai, Wenyi;Wu, Jianfeng;Xi, Chuanwu;Ashe, Arthur J., III;Meyerhoff, Mark E.
通讯作者：
Meyerhoff, Mark E.
影响因子：
--
作者：
Handa, Y;Kaneko, M;Kubota, T
通讯作者：
Kubota, T
影响因子：
6.7
作者：
Hoepfner, Dominic;Helliwell, Stephen B.;Movva, N. Rao
通讯作者：
Movva, N. Rao
影响因子：
4
作者：
Alajlouni, Ruba A.;Seleem, Mohamed N.
通讯作者：
Seleem, Mohamed N.
DOI：
10.3109/14756360903179419
发表时间：
2010-06-01
影响因子：
5.6
作者：
Billack, Blase;Pietka-Ottlik, Magdalena;Lau-Cam, Cesar
通讯作者：
Lau-Cam, Cesar