Zheng Weihao, Liang Yujie, Zhao Hui, Zhang Jianing, Li Zigang
Key Lab of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055 (China).
Chembiochem. 2015 May 4;16(7):1035-40. doi: 10.1002/cbic.201500003. Epub 2015 Mar 24.
SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatases (Stk1/Stp1) were found to modulate phosphorylation of these transcriptional regulators as well as staphylococcal virulence. Importantly, an stp1-deficient strain showed significant virulence reduction in mice, indicative of Stp1 as a potential drug target. Here, we report that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in S. aureus. MDSA is a more-potent inhibitor (IC50 =9.68 ± 0.52 μM) of Stp1 than commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to develop new approaches for reducing staph virulence by targeting Stp1.
SarA（葡萄球菌辅助蛋白A）、MgrA（全局转录调节因子A的MarR家族）和SarZ（SarA的旁系同源物）在调节金黄色葡萄球菌的毒力、耐药性和自溶方面发挥着关键作用。最近，发现类真核丝氨酸/苏氨酸激酶/磷酸酶（Stk1/Stp1）可调节这些转录调节因子的磷酸化以及葡萄球菌的毒力。重要的是，一株stp1缺陷菌株在小鼠中显示出显著的毒力降低，这表明Stp1是一个潜在的药物靶点。在此，我们报告称，MgrA抑制剂MDSA通过抑制金黄色葡萄球菌中的Stp1来增强SarA/MgrA的磷酸化。MDSA是一种比常用磷酸酶抑制剂更有效的Stp1抑制剂（IC50 = 9.68 ± 0.52 μM）。我们预计MDSA可能成为一种先导化合物，用于开发通过靶向Stp1来降低葡萄球菌毒力的新方法。
