Abstract
Ebselen (2‐phenyl‐1,2‐benzisoselenazol‐3(2__H__)‐one) is a selenium‐containing antioxidant demonstrating anti‐inflammatory and cytoprotective properties in mammalian cells and cytotoxicity in lower organisms. The mechanism underlying the antimicrobial activity of ebselen remains unclear. It has recently been proposed that, in lower organisms like yeast, the plasma membrane H^+^‐ATPase (Pma1p) could serve as a potential target for this synthetic organoselenium compound. Using yeast and bacteria, the present study found ebselen to inhibit microbial growth in a concentration‐ and time‐dependent manner, and yeast and Gram‐positive bacteria to be more sensitive to this action (IC~50~ ∼ 2–5 μM) than Gram‐negative bacteria (IC~50~ < 80 μM). Washout experiments and scanning electron microscopic analysis revealed ebselen to possess fungicidal activity. In addition, ebselen was found to inhibit medium acidification by PMA1‐proficient haploid yeast in a concentration‐dependent manner. Additional studies comparing PMA1 (+/−) and PMA1 (+/+) diploid yeast cells revealed the mutant to be more sensitive to treatment with ebselen than the wild type. Ebselen also inhibited the ATPase activity of Pma1p from S. cerevisae in a concentration‐dependent manner. The interaction of ebselen with the sulfhydryl‐containing compounds L‐cysteine and reduced glutathione resulted in the complete and partial prevention, respectively, of the inhibition of Pma1p ATPase activity by ebselen. Taken together, these results suggest that the fungicidal action of ebselen is due, at least in part, to interference with both the proton‐translocating function and the ATPase activity of the plasma membrane H^+^‐ATPase. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:252–264, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20189