以3M-Sortase A蛋白酶为靶点的抗感染药物的设计、合成及活性研究

革兰氏阳性菌是最常见的引起医院感染的病原菌，这些细菌主要通过其细胞表面的一些特异毒性蛋白识别宿主的组织细胞表面蛋白而感染宿主。而分选酶Sortase A是一种蛋白酶对金黄色葡萄球菌的多种毒性特异蛋白锚定到细菌细胞壁上起了关键作用，已成为抗感染药物研究的重要靶点。目前所报道Sortase A蛋白酶的抑制剂并未对体内感染表现出明显抑制作用。通过前期研究，我们以Sortase A蛋白酶突变体(3M-sortase A) 为靶点，经高通量筛选获得数个化合物可在细胞水平有效抑制金黄色葡萄球菌的感染。本项目拟基于前期筛选到的抗金黄色球菌感染的先导化合物及Sortase A的蛋白结构特征，结合计算辅助药物设计方法，设计并合成一系列苯并噁唑类新化合物。通过酶和细胞水平的活性反馈探索新化合物的构效关系，指导合成具有更高活性抗金黄色葡萄球菌感染的化合物，并探索作用机制，为研究新型的抗感染药物提供理论依据。

Infectious gram-positive bacteria are a major concern in hospitals. These human pathogens employ a array of wall anchored virulence factors to recognize and adhere to host cells.The staphylococcus aureus sortase A is a transpeptidase that attaches surface virulence proteins to the cell wall of bacteria and are thought to be a good target for new antibiotics.However, several lead compound showed weak anti-infactious effect in vivo assay. Recently, we found that monomer sortase A is the active form and got five potential in-vivo anti-infectious chemical inhibitors by a high throughput screening method.Here, we plan to synthesize and evaluate these related-chemicals by a reasonal design manner,based on analysis of the known complex struture of sortase A and obtained lead compounds. Finnally, we hope to develope unique sortase A inhibitors that function in anti-infection of grans-postive pathogens, and explore its inhibiton mechanism in this research.