title: Identification of Ebsulfur Analogues with Broad-Spectrum Antifungal Activity.
abstract: Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Current antifungal drugs are helpful, but are insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. The ebselen scaffold has been evaluated in clinical trials and has been shown to be safe in humans. This makes ebselen an attractive scaffold for facile translation from bench to bedside. We recently reported a library of ebselen-inspired ebsulfur analogues with antibacterial properties, but their antifungal activity has not been characterized. In this study, we repurposed ebselen, ebsulfur, and 32 additional ebsulfur analogues as antifungal agents by evaluating their antifungal activity against a panel of 13 clinically relevant fungal strains. The effect of induction of reactive oxygen species (ROS) by three of these compounds was evaluated. Their hemolytic and cytotoxicity activities were also determined using mouse erythrocytes and mammalian cells. The MIC values of these compounds were found to be in the range of 0.02-12.5 μg mL(-1) against the fungal strains tested. Notably, yeast cells treated with our compounds showed an accumulation of ROS, which may further contribute to the growth-inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536-0596, USA.
authors.forename: Huy X
authors.initials: HX
authors.lastname: Ngo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536-0596, USA.
authors.forename: Sanjib K
authors.initials: SK
authors.lastname: Shrestha
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536-0596, USA. sylviegtsodikova@uky.edu.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001230:Aspergillus / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D015725:Fluconazole / Q000494:pharmacology; D057809:HEK293 Cells; D006461:Hemolysis; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D006574:Heterocyclic Compounds, 2-Ring; D017382:Reactive Oxygen Species; D013844:Thiazoles; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole; D000666:Amphotericin B; D015725:Fluconazole; D065819:Voriconazole
keywords: Aspergillus; Candida; ROS production; benzisothiazolinone; ebselen