期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1861, 期 1, 页码 3002-3010出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2016.09.029
关键词
Ebselen; Antifungal activity; Glutathione; ROS production; C. elegans
资金
- Bindley Bioscience Center Fellow program
- Purdue University Center for Cancer Research, NIH [P30 CA023168]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R56AI114861]
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 Comtococcus spp., at concentrations ranging from 0.5 to 2 mu g/ml. Ebselen rapidly eradicates a high fungal inoculum within 2 h 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. (C) 2016 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据