耐甲氧西林金黄色葡萄球菌（MRSA）对多种结构类型的抗生素相继耐药，新型抗MRSA药物的研发尤为迫切。天然产物阿扎霉素F5a为链霉菌代谢所产36元大环内酯的代表性化合物，申请人2012年首次报道其相对构型后，发现其具有显著的抗MRSA活性，且前期研究分析显示阿扎霉素F5a作用于MRSA的细胞膜磷脂，然而其分子机制和该化合物的绝对构型尚未明确。基于此，该课题拟采用现代绝对构型研究的NMR法，对阿扎霉素F5a进行合理降解，随后测定降解产物的绝对构型，并结合特定片段的模型化合物合成及NMR数据比对，反过来构建和确证阿扎霉素F5a的绝对构型；同时，分别结合以磷脂酰甘油和MRSA细胞膜脂质制备的模拟生物膜，采用拉曼光谱、原子力显微镜、差示扫描量热和NMR等现代波谱和生物物理技术，并借助分子动力学模拟，对阿扎霉素F5a抗MRSA细胞膜磷脂作用的分子机制进行深入研究，为新型抗MRSA药物的研发打下基础。

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to a variety of structural types of antibiotics, and the research and development of new anti-MRSA drugs is particularly urgent. Azalomycin F5a is a typical 36-membered macrolide produced by some streptomyces strains. After the relative configuration of azalomycin F5a was first assigned in 2012, it's remarkable anti-MRSA activity through acting on the cell membrane phospholipids of MRSA was discovered by us. While the molecular mechanism of azalomycin F5a against MRSA was not clear, and it's absolute configurarion was not assigned. Based on this, the absolute configuration of azalomycin F5a will be assigned by NMR method in this project. First, the specific derivatives and Mosher esters of degradation products derived from azalomycin F5a, together with the model compounds of special fragments, will be synthesized. Secondly, the absolute configurations of degradation products will be determined by NMR method and by comparing their NMR data with those of model compounds. Finally, the absolute configuration of azalomycin F5a will be assigned from those of degradation products. Simultaneously, combined with the biomembrane models respectively prepared by phosphatidylglycerol and the cell membrane lpids extracted from exponential phase MRSA, the molecular mechanism of azalomycin F5a acting on the cell membrane phospholipids will be researched by modern spectroscopic and biophysical techniques, such as raman spectroscopy, atomic force microscopy, differential scanning calorimetry and nuclear magnetic resonance, and by molecular dynamics simulation. Through above researches, a solid foundation will be established for the research and development of new anti-MRSA drug.