环化小檗碱类抗MRSA活性探针构建及直接靶标确证

MRSA感染成为全球临床面临的棘手难题。我们自主创新、全新结构骨架环化小檗碱（CBBR）组成了一类优异的抗MRSA化合物，部份化合物的MIC值低至0.125 μg/mL，优于左氧氟沙星百余倍。但其直接作用靶标尚不清楚，独特的化学生物学机制有待探索。.本项目拟在一系列原创性工作基础上，结合前期构效关系，以抗MRSA活性为导向，经多轮结构修饰与优化，设计合成不少于30个结构类型不同的CBBR光亲和探针，优选出活性高、特异性强的探针2–3个。继而以活性探针为化学工具，采用ABPP等化学蛋白质组学技术，垂钓并确证CBBR类抗MRSA直接靶蛋白，阐明其与靶标活性腔的键合模式，完成其抗MRSA的化学生物学整体研究。同时为抗MRSA创新药物的发现提供一个全新靶点，以此提升我国抗感染药物源头创新能力，为应对临床超级耐药菌的突发性感染与流行提供充足的战略物质储备。

Infection caused by methicillin-resistant Staphylococcus aureus (MRSA) has become one of the trickiest problems in the global clinic. Our innovative cycloberbine (CBBR) derivatives with a new structure scaffold constitute a class of excellent anti-MRSA compounds. The MIC values of some compounds were as low as 0.125 μg/mL, 100 times lower than that of levofloxacin. However, its direct target against MRSA remains unclear, and its chemical biological mechanism remains to be explored. .Based on these original work, combined with previous structure-activity relationship, at least 30 anti-MRSA CBBR photoaffinity probes with different structural types will be designed and synthesized through multiple rounds of structural modification and optimization, and 2-3 probes with high activity and strong specificity will be selected out. Next, taking them as chemical tools, the direct target(s) of CBBR derivatives against MRSA will be captured and identified by chemical proteomics technology, for example ABPP. The binding mode between CBBR and the active cavity of target macromolecule will be illustrated, so as to complete the chemical and biological integral study of anti-MARSA CBBR derivatives. Meanwhile, this project will probably provide a new target for the discovery of innovative anti-MRSA drugs. Overall, this study will enhance the original innovation ability of anti-infective drugs in China and provide sufficient material basis for the battle against the sudden spreading of infections caused by superbugs like MRSA in clinic.