1] State Key Laboratory of Molecular Biology, Center for RNA research, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai 200031, China [2].
Sci Rep. 2013;3:2475. doi: 10.1038/srep02475.
Streptococcus pneumoniae causes bacterial pneumonia with high mortality and morbidity. The emergency of multidrug-resistant bacteria threatens the treatment of the disease. Leucyl-tRNA synthetase (LeuRS) plays an essential role in cellular translation and is an attractive drug target for antimicrobial development. Here we report the compound ZCL039, a benzoxaborole-based derivative of AN2690, as a potent anti-pneumococcal agent that inhibits S. pneumoniae LeuRS (SpLeuRS) activity. We show using kinetic, biochemical analyses combined with the crystal structure of ZCL039-AMP in complex with the separated SpLeuRS editing domain, that ZCL039 binds to the LeuRS editing active site which requires the presence of tRNA(Leu), and employs an uncompetitive inhibition mechanism. Further docking models establish that ZCL039 clashes with the eukaryal/archaeal specific insertion I4ae helix within editing domains. These findings demonstrate the potential of benzoxaboroles as effective LeuRS inhibitors for pneumococcus infection therapy, and provide future structure-guided drug design and optimization.
肺炎链球菌可引起高死亡率和高发病率的细菌性肺炎。多药耐药菌的出现威胁着该疾病的治疗。亮氨酰-tRNA 合成酶（LeuRS）在细胞翻译中起着至关重要的作用，是抗菌药物开发的一个有吸引力的药物靶点。在这里，我们报告了化合物 ZCL039，一种基于苯并恶唑硼的 AN2690 衍生物，作为一种有效的抗肺炎链球菌药物，可抑制肺炎链球菌亮氨酰-tRNA 合成酶（SpLeuRS）的活性。我们通过动力学、生化分析以及 ZCL039-AMP 与分离的 SpLeuRS 编辑结构域复合物的晶体结构，表明 ZCL039 结合到 LeuRS 编辑活性位点，该活性位点需要 tRNA(Leu)的存在，并采用非竞争性抑制机制。进一步的对接模型表明，ZCL039 与编辑结构域内的真核/古菌特异性插入 I4ae 螺旋发生冲突。这些发现表明苯并恶唑硼类化合物作为肺炎球菌感染治疗的有效 LeuRS 抑制剂具有潜力，并为未来的基于结构的药物设计和优化提供了依据。
