Shankar Thangamani1, Hassan E Eldesouky1, Haroon Mohammad1, Pete E Pascuzzi2, Larisa Avramova3, Tony R Hazbun4, Mohamed N Seleem5. 1. Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA. 2. Faculty in Libraries, Purdue University, West Lafayette, IN 47906, USA. 3. Bindley Bioscience Center, Purdue University, West Lafayette, IN 47906, USA. 4. Bindley Bioscience Center, Purdue University, West Lafayette, IN 47906, USA; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47906, USA. Electronic address: thazbun@purdue.edu. 5. Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA; Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA. Electronic address: mseleem@purdue.edu.
Abstract
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. Copyright Â
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. Copyright Â
Authors: Hassan E Eldesouky; Ehab A Salama; Nadia A Lanman; Tony R Hazbun; Mohamed N Seleem Journal: Antimicrob Agents Chemother Date: 2020-12-16 Impact factor: 5.191
Authors: Gina Wall; Ashok K Chaturvedi; Floyd L Wormley; Nathan P Wiederhold; Hoja P Patterson; Thomas F Patterson; José L Lopez-Ribot Journal: Antimicrob Agents Chemother Date: 2018-09-24 Impact factor: 5.191
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