Evaluation of the antimicrobial activity of ebselen: role of the yeast plasma membrane H+-ATPase.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-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 (IC50 approximately 2-5 microM) than Gram-negative bacteria (IC50 < 80 microM). 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. cerevisiae 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.
Chan
Grace
G
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, USA.
Hardej
Diane
D
Santoro
Michelle
M
Lau-Cam
Cesar
C
Billack
Blase
B
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology*; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D054833:Isoindoles; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D016566:Organoselenium Compounds / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development / Q000648:ultrastructure; D013997:Time Factors
D000900:Anti-Bacterial Agents; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D006180:Proton-Translocating ATPases