生物膜是耐甲氧西林金黄色葡萄球菌（MRSA）产生多重耐药的重要机制，与其形成密切相关的脂磷壁酸（LTA）已逐渐成为新型抗MRSA药物研发的重要靶标。课题组在研究新型抗MRSA天然产物阿扎霉素F5a作用于细胞膜磷脂和消除生物膜机制时，首次发现其可靶向脂磷壁酸合酶（LtaS）抑制LTA的合成。基于此，该课题将模拟MRSA细胞内LtaS催化合成LTA的生化过程，采用免疫印迹和LC-MS等现代生化研究的方法和技术，对LtaS蛋白脂质体中阿扎霉素F5a抑制LTA的合成进行研究；然后采用ESI-MS、荧光光谱和LC-MS等现代小分子与蛋白作用的研究方法和技术，对体外孵化体系中阿扎霉素F5a抑制LTA合成及与eLtaS作用的结合位点、结合强度和作用力类型等进行深入研究，再借助分子动力学模拟的佐证与沟通，系统阐明阿扎霉素F5a靶向LtaS抑制LTA合成的机制，为新型高效抗MRSA药物的研发打下坚实基础。

Biofilm is an important mechanism for methicillin-resistant Staphylococcus aureus (MRSA) being resistant to a variety of structural types of antibiotics, and closely related to which a cell envelope molecule lipoteichoic acid (LTA) has gradually become an important target for the development of new anti-MRSA drugs. Azalomycin F5a, a new anti-MRSA natural product, was discovered to target lipoteichoic acid synthetase (LtaS) to inhibit lipoteichoic acid synthesis when its mechanism of acting on cell membrane phospholipids and eradicating biofilm had been explored by us. Thereout, stimulating the biochemical process of LtaS synthesizing LTA, the detail of azalomycin F5a targeting LtaS to inhibit LTA synthesis in proteoliposomes containing LtaS were researched using modern biochemical methods and techniques such as immunoblotting and LC-MS in this project. Then, using modern methods and techniques such as ESI-MS, fluorescence spectroscopy and LC-MS for researching on the interactions between small molecules and proteins, the detail of azalomycin F5a targeting LtaS to inhibit LTA synthesis, and the binding sites, interaction force types and space modes between azalomycin F5a and eLtaS were studied in vitro incubation system. With the help of molecular dynamics simulation between azalomycin F5a and LtaS, this will clarify the mechanism of azalomycin F5a targeting LtaS to inhibit LTA synthesis, and reveal the intrinsic causes of its anti-MRSA and eradicating MRSA biofilm. Hereafter, a solid basis for the research and development of novel and efficient anti-MRSA drugs will be established.