Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain
Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain
复制标题
DOI：
10.1021/jm061068d
复制
发表时间：
2006-12-28
影响因子：
7.3
通讯作者：
Aldrich, Courtney C.
中科院分区：
文献类型：
--
作者：
Somu, Ravindranadh V.;Wilson, Daniel J.;Aldrich, Courtney C.
结核病是世界上由细菌病原体引起的传染病死亡的主要原因。我们以前证明，腺苷酸化酶MbtA的双底物抑制剂，这是负责分枝杆菌素生物合成的第二步，表现出有效的抗结核活性。在这里，我们系统地调查的结构-活性关系的双底物抑制剂糖基结构域，导致在识别的碳环类似物，具有K-I（app）值为2.3 nM和MIC 99值为1.56 μ M对M。结核病H37 Rv. SAR数据表明，双底物抑制剂利用转运蛋白进入分枝杆菌细胞包膜的有趣的可能性。此外，我们报告了改进的条件MbtA的表达和生化分析，表明MbtA遵循随机顺序酶机制的腺苷酸化半反应。
Tuberculosis is the leading cause of infectious disease mortality in the world by a bacterial pathogen. We previously demonstrated that a bisubstrate inhibitor of the adenylation enzyme MbtA, which is responsible for the second step of mycobactin biosynthesis, exhibited potent antitubercular activity. Here we systematically investigate the structure-activity relationships of the bisubstrate inhibitor glycosyl domain resulting in the identification of a carbocyclic analogue that possesses a K-I(app) value of 2.3 nM and MIC99 values of 1.56 mu M against M. tuberculosis H37Rv. The SAR data suggest the intriguing possibility that the bisubstrate inhibitors utilize a transporter for entry across the mycobacterial cell envelope. Additionally, we report improved conditions for the expression of MbtA and biochemical analysis, demonstrating that MbtA follows a random sequential enzyme mechanism for the adenylation half-reaction.