矢车菊素抑制金葡菌丝氨酸/苏氨酸蛋白磷酸酶(Stp1)分子机制确证及构效关系分析

金黄色葡萄球菌是一种重要的人兽共患机会致病菌，可引起多种动物和人的致死性感染，如肺炎、脑膜炎、动物流产、死胎等。随着耐甲氧西林金黄色葡萄球菌的出现以及新抗生素研发效率的降低等因素进一步增加了其治疗难度。丝氨酸/苏氨酸蛋白磷酸酶(Stp1)在金葡菌致病过程中作为全局性的调节因子参与调解毒素蛋白表达。Stp1缺失株毒素蛋白表达显著下降，几乎无致病性，因此Stp1是抗金葡菌毒力药物研发最有希望的靶标之一。本课题组通过Stp1活性筛选平台发现多种抗Stp1天然化合物，其中矢车菊素抑制效果最佳，但对其表达并无影响。这一结果提示矢车菊素可直接作用于Stp1从而抑制其活性。本课题拟在前期研究的基础上，应用分子模拟、等离子体共振以及X-射线晶体学等技术确证矢车菊素抗Stp1结合位点，阐明其分子互作机制并进行构效关系分析，验证矢车菊素对金葡菌感染小鼠的保护作用，以期为以Stp1为靶标的创新药物研发奠定基础。

Staphylococcus aureus is an important bacterial zoonotic pathogen. It can cause a variety of lethal infections in animals and human, such as pneumonia, meningitis, animal abortion, stillbirth, and so on. Staphylococcus aureus is a significant human pathogen. The growing emergence of methicillin-resistant S. aureus strains and a decrease in the discovery of new antibiotics warrant the search for new therapeutic strategies to combat infections. Serine/threonine phosphatase (Stp1) can mediate the expression of the virulent protein, cell wall structure and drug-resistance during the pathogenic process of Staphylococcus aureus. The expression of virulence protein of Stp1 deletion strain decreased significantly, and it almost has no pathogenicity. Therefore, Stp1 is one of the most promising targets for the development of virulent drugs against Staphylococcus aureus. In preliminary studies, we found that several natural compounds could inhibit bio-activity of Stp1, and Cyanidin has the best inhibition effect without the effect on its expression, implying that Cyanidin can interact with Stp1 directly and inhibit its activity. On the basis of previous results, this project is intended to further identify the binding sites, explore interaction mechanism of Cyanidin with Stp1 and analyze the quantitative structure-activity relationship via molecular modeling, SPR and X-ray crystallography; and further investigate its therapeutic performance of Staphylococcal pneumonia in a mouse model. The study is expected to lay the foundation for the development of drugs that target on Stp1.