生物膜（Biofilm）是耐甲氧西林金黄色葡萄球菌（MRSA）产生多重超强耐药的重要机制，消除生物膜的新型抗MRSA药物研发尤为迫切。申请人在报道天然产物阿扎霉素F5a的抗MRSA活性和协同三甲基氢醌抗MRSA作用后，发现该化合物具有显著的消除MRSA生物膜作用，且C-29位的Schiff碱修饰可显著增强其抗MRSA活性。基于此，该课题以阿扎霉素F5a为起始物，采用杂合抗生素、生物电子等排等现代药物设计思路和Click chemistry高效合成法，在C-29位以Schiff碱的形式引入含对苯酚或对苯醌的侧链，并测定所得衍生物的抗MRSA生物膜作用；同时采用凝胶电泳、HPLC-MS/MS和蛋白质印迹法等现代蛋白质组研究方法和技术，结合蛋白质数据库检索等，对阿扎霉素F5a干预MRSA生物膜前后的胞外蛋白质组进行系统研究，以阐明其消除生物膜的深入机制，为新型高效抗MRSA药物的研发打下基础。

Biofilm was an important mechanism for methicillin-resistant Staphylococcus aureus (MRSA) being noticeable resistant to a variety of structural types of antibiotics, and the research and development of new anti-MRSA drugs eradicating biofilm is particularly urgent. After the anti-MRSA activity of a natural product azalomycin F5a and its synergistic anti-MRSA activity together with trimethylhydroquinone were reported by us, the remarkable activity eradicating MRSA biofilm of azalomycin F5a was discovered while the mechanism is still unknown, and its anti-MRSA activity could be improved by forming Schiff base at C-29 position. Based on these, using azalomycin F5a as an initiator, some derivatives introduced hydroquinone or p-quinone group side chain at C-29 position were designed by modern drug design principle such as hybrid antibiotics and bioisostere, and which were achieved by click chemistry. Next, the anti-MRSA biofilm activities of these azalomycin F5a derivatives were determined. Simultaneously, the extracellular proteomes after/before adding azalomycin F5a into the culture contained MRSA biofilm were researched using gelelectrophoresis, HPLC-MS/MS combined protein database search and subcellular localization, and Western Blot for the in-depth mechanism eradicating biofilm of azalomycin F5a. Hereafter, a solid basis for the research and development of novel and efficient anti-MRSA drugs eradicating biofilm will be established.