Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione
Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione
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DOI：
10.1096/fj.12-223305
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发表时间：
2013-04-01
期刊：
影响因子：
4.8
通讯作者：
Holmgren, Arne
中科院分区：
文献类型：
--
作者：
Lu, Jun;Vlamis-Gardikas, Alexios;Holmgren, Arne
抗生素耐药性的增加使得鉴定新的抗菌原理成为一项紧迫的任务。硫氧还蛋白系统包括硫氧还蛋白还原酶（TrxR）、硫氧还蛋白（Trx）和NADPH，其在细胞DNA合成和抗氧化应激中起关键作用。值得注意的是，TrxR在哺乳动物和细菌中的结构和机制非常不同。Ebselen [2-phenyl-1，2 benzisoselenazol-3（2 H）-one]是一种众所周知的抗氧化剂，也是哺乳动物TrxR和Trx的底物，通过未知的机制对耐甲氧西林金黄色葡萄球菌快速杀菌。我们发现依布硒啉是大肠杆菌TrxR的竞争性抑制剂，通过与酶的活性位点二硫醇反应，Ki为0.52 +/- 0.13 μ M。缺乏谷胱甘肽（GSH）和谷氧还蛋白（其中TrxR和Trx是DNA合成所必需的）的细菌对依布硒啉特别敏感。在生长抑制E.大肠杆菌菌株，Trx 1和Trx 2被氧化，表明通过硫氧还蛋白的电子传递被阻断。Ebselen及其硫类似物ebsulfur对GSH阴性病原体具有杀菌作用。Ebsulfur抑制临床分离的幽门螺杆菌菌株，最小抑制浓度值低至0.39 μ g/ml。这些结果表明，使用苯并异硒唑和苯并异噻唑衍生物，细菌Trx和TrxR是可行的抗菌药物靶标。卢，J，Vlamis-Gardikas，A.，Kandasamy，K.，赵，R.，Gustafsson，T. N.，Engstrand，L.，Hoffner，S.，恩格曼湖霍姆格伦A.细菌硫氧还蛋白还原酶的抑制：一种针对缺乏谷胱甘肽细菌的抗生素机制。FASEB J.27，1394-1403（2013）。www.fasebj.org
Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria. Ebselen [2-phenyl-1,2 benzisoselenazol-3(2H)-one], a well-known antioxidant and a substrate for mammalian TrxR and Trx, is rapidly bacteriocidal for methicillin-resistant Staphylococcus aureus by an unknown mechanism. We have discovered that ebselen is a competitive inhibitor of Escherichia coli TrxR with a K-i of 0.52 +/- 0.13 mu M, through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx are essential for DNA synthesis, were particularly sensitive to ebselen. In growth-inhibited E. coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH-negative pathogens. Ebsulfur inhibited a clinically isolated Helicobacter pylori strain with a minimum inhibitory concentration value as low as 0.39 mu g/ml. These results demonstrate that bacterial Trx and TrxR are viable antibacterial drug targets using benzisoselenazol and benzisothiazol derivates.-Lu, J., Vlamis-Gardikas, A., Kandasamy, K., Zhao, R., Gustafsson, T. N., Engstrand, L., Hoffner, S., Engman, L., Holmgren, A. Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione. FASEB J. 27, 1394-1403 (2013). www.fasebj.org