Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis
Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis
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DOI：
10.1016/j.bbagen.2016.03.013
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发表时间：
2016-06-01
影响因子：
3
通讯作者：
Holmgren, Arne
中科院分区：
文献类型：
--
作者：
Gustafsson, Tomas N.;Osman, Harer;Holmgren, Arne
背景资料：炭疽芽孢杆菌是炭疽病的病原体，炭疽病是一种在其侵袭形式下死亡率非常高的疾病。方法：我们研究了一些作为B抑制剂的依布硒啉类似物。结果：该系列中最有效的化合物对纯酶的IC 50值低至70 nM，对B的最小抑制浓度（MIC）低至0.4 μ M（0.12 μ g/ml）。枯草杆菌1.5 μ M（0.64 μ g/ml）;金黄色葡萄球菌，对于B为2 μ M（0.86 μ g/ml）。10 μ g/ml;结核发现最小杀菌浓度（MBC）为MIC的1-1.5倍，表明具有一般性、类别依赖性杀菌作用模式。结合细菌学和酶学数据被用来构建一个初步的结构-活性-苯并异硒唑类化合物的关系。当S. aureus和B. subtilis暴露于依布硒啉，我们不能在固体和液体培养基中分离抗性突变体，这表明高抗性barrier.Conclusions：这些结果表明依布硒啉及其类似物可以被开发成新的抗生素类，用于治疗由B引起的感染。anthracis，S. aureus，M.结核病和其他临床重要细菌。此外，对耐药性发展的高障碍是令人鼓舞的进一步药物开发。一般意义：我们已经确定了从B的硫氧还蛋白系统。炭疽作为新的药物靶标，以及依布硒啉及其类似物作为靶向几种重要的人类病原体的潜在的新类别抗生素。(C)2016爱思唯尔B. V.保留所有权利。
Background: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms.Methods: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis.Results: The most potent compounds in the series gave IC50 values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 mu M (0.12 mu g/ml) for B. subtilis,1.5 mu M (0.64 mu g/ml) for S. aureus, 2 mu M (0.86 mu g/ml) for B. cereus and 10 mu g/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier.Conclusions: These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development.General significance: We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens. (C) 2016 Elsevier B.V. All rights reserved.