Evaluation of the antimicrobial activity of ebselen:: Role of the yeast plasma membrane H+-ATPase
Evaluation of the antimicrobial activity of ebselen:: Role of the yeast plasma membrane H+-ATPase
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DOI：
10.1002/jbt.20189
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Billack, Blase
中科院分区：
文献类型：
--
作者：
Chan, Grace;Hardej, Diane;Billack, Blase
Ebselen（2-苯基-1，2-苯并异硒唑-3（2 H）-酮）是一种含硒抗氧化剂，在哺乳动物细胞中具有抗炎和细胞保护特性，在低等生物中具有细胞毒性。依布硒啉抗菌活性的机制尚不清楚。最近有人提出，在低等生物如酵母中，质膜HI-ATPase（Pmalp）可以作为这种合成有机硒化合物的潜在靶点。使用酵母和细菌，本研究发现依布硒啉以浓度和时间依赖性方式抑制微生物生长，并且酵母和革兰氏阳性细菌对该作用（IC 50类似于2-5 μ M）比革兰氏阴性细菌更敏感（IC 50> 80 μ M）。洗出实验和扫描电镜分析表明依布硒啉具有杀菌活性。此外，发现依布硒啉以浓度依赖性方式抑制PMA 1-精通单倍体酵母的培养基酸化。比较PMA 1（+/-）和PMA 1（+/+）二倍体酵母细胞的其他研究显示，突变体比野生型对依布硒啉处理更敏感。依布硒啉还能抑制S. cerevisae以浓度依赖性方式。依布硒啉与含巯基化合物L-半胱氨酸和还原型谷胱甘肽的相互作用分别导致依布硒啉对Pmalp ATP酶活性的抑制作用完全和部分预防。综上所述，这些结果表明，依布硒啉的杀菌作用是由于，至少部分地，与质子转运功能和质膜H+-ATP酶的ATP酶活性的干扰。(c)2007 Wiley Periodicals，Inc.
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 HI-ATPase (Pmalp) 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 similar to 2-5 mu M) than Gram-negative bacteria IC50 > 80 M). 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 Pmalp 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 Pmalp 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. (c) 2007 Wiley Periodicals, Inc.