...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Applied Microbiology and Biotechnology >Screening of antitubercular compound library identifies novel shikimate kinase inhibitors of Mycobacterium tuberculosis
【24h】

Screening of antitubercular compound library identifies novel shikimate kinase inhibitors of Mycobacterium tuberculosis

机译：抗结核化合物文库的筛选鉴定了结核分枝杆菌的新型sh草酸激酶抑制剂

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Shikimate kinase of Mycobacterium tuberculosis is involved in the biosynthesis of aromatic amino acids through shikimate pathway. The enzyme is essential for the survival of M. tuberculosis and is absent from mammals, thus providing an excellent opportunity for identifying new chemical entities to combat tuberculosis with a novel mechanism of action. In this study, an antitubercular library of 1000 compounds was screened against M. tuberculosis shikimate kinase (MtSK). This effort led to the identification of 20 inhibitors, among which five promising leads exhibited half maximal inhibitory concentration (IC50) values below 10 mu M. The most potent inhibitor ("5631296") showed an IC50 value of 5.10 mu M +/- A 0.6. The leads were further evaluated for the activity against multidrug-resistant (MDR)-TB, Gram-positive and Gram-negative bacterial strains, mode of action, docking simulations, and combinatorial study with three frontline anti-TB drugs. Compound "5491210" displayed a nearly synergistic activity with rifampicin, isoniazid, and ethambutol while compound "5631296" was synergistic with rifampicin. In vitro cytotoxicity against HepG2 cell line was evaluated and barring one compound; all were found to be non-toxic (SI > 10). In order to rule out mitochondrial toxicity, the promising inhibitors were also evaluated for cell cytotoxicity using galactose medium where compounds "5631296" and "5122752" appeared non-toxic. Upon comprehensive analysis, compound "5631296" was found to be the most promising MtSK inhibitor that was safe, synergistic with rifampicin, and bactericidal against M. tuberculosis.
机译：结核分枝杆菌的草酸激酶通过through草酸途径参与芳香族氨基酸的生物合成。该酶对于结核分枝杆菌的生存是必不可少的，并且在哺乳动物中是不存在的，因此提供了极好的机会来鉴定具有新颖作用机制的新化学实体，以抗击结核病。在这项研究中，针对结核分枝杆菌sh草酸激酶（MtSK）筛选了1000种化合物的抗结核文库。这项工作导致鉴定出20种抑制剂，其中五种有前途的潜在药物在10 µM以下的半数最大抑制浓度（IC50）值为一半。最有效的抑制剂（“ 5631296”）的IC50值为5.10 µM +/- A 0.6。进一步评估了线索对三种耐多药结核病（MDR），革兰氏阳性和革兰氏阴性细菌菌株的活性，作用方式，对接模拟和组合研究。化合物“ 5491210”显示与利福平，异烟肼和乙胺丁醇几乎具有协同活性，而化合物“ 5631296”与利福平具有协同作用。评价了对HepG2细胞系的体外细胞毒性，并排除了一种化合物。全部被发现是无毒的（SI> 10）。为了排除线粒体毒性，还使用半乳糖培养基（化合物“ 5631296”和“ 5122752”显得无毒）评估了有前途的抑制剂的细胞毒性。经综合分析，发现化合物“ 5631296”是最有前途的MtSK抑制剂，它是安全的，与利福平有协同作用，并且对结核分枝杆菌具有杀菌作用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号