Azalomycin F-5a, a polyhydroxy macrolide binding to the polar head of phospholipid and targeting to lipoteichoic acid to kill methicillin-resistant Staphylococcus aureus
Azalomycin F-5a, a polyhydroxy macrolide binding to the polar head of phospholipid and targeting to lipoteichoic acid to kill methicillin-resistant Staphylococcus aureus
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Azalomycin F-5a，一种多羟基大环内酯，与磷脂的极性头结合，靶向脂磷壁酸，杀死耐甲氧西林金黄色葡萄球菌
DOI：
10.1016/j.biopha.2018.11.067
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发表时间：
2019
影响因子：
7.5
通讯作者：
Liu Qianru
中科院分区：
文献类型：
--
作者：
Yuan Ganjun;Xu Li;Xu Xuejie;Li Peibo;Zhong Qiwang;Xia Hailin;Hu Yamei;Li Pingyi;Song Xiaoyuan;Li Junfang;Liu Qianru
阿扎霉素F5 a是由链霉菌产生的一种多羟基大环内酯类抗生素。我们的初步研究表明，它可能通过增加细胞膜的通透性来杀灭耐甲氧西林金黄色葡萄球菌（MRSA），细胞膜磷脂可能是其重要作用靶点。为了证实这一点，进行了膜渗透性测定，并通过荧光染色可视化，然后使用衰减全反射傅立叶变换红外光谱和31 P核磁共振技术测定阿扎霉素F5 a与由1，2-二十六烷酰基-sn-甘油基-3-磷酸-（1 '-rac-甘油）（DPPG）制备的模型膜之间的详细相互作用。结果表明，阿扎霉素F5 a与模型膜之间存在较强的相互作用，尤其是与磷脂的极性头之间。为了进一步研究阿扎霉素F5 a与DPPG和赖氨酰DPPG的相互作用，采用Amber 16软件包对阿扎霉素F5 a与DPPG和赖氨酰DPPG的相互作用进行了分子动力学模拟。阿扎霉素F5 a的内酯环与DPPG或赖氨酰-DPPG的极性头之间有很强的相互作用。阿扎霉素F5 a胍基侧链在磷脂双分子层外有较大的分布概率，特别是当可能锚定在细胞质膜上的阴离子分子时。因此，采用微量肉汤稀释法研究了脂磷壁酸（LTA）与阿扎霉素F5的相互作用。结果表明，LTA可抑制阿扎霉素F5 a诱导的MRSA裂解。这推断阿扎霉素F5 a（更可能是其胍基侧链）与LTA之间存在一些相互作用。因此，阿扎霉素F5 a增加MRSA细胞膜通透性的作用可能是通过其内酯环与磷脂极性头的结合和其胍基侧链与LTA的靶向协同作用实现的，并最终导致MRSA细胞的自溶。
Azalomycin F5awas a polyhydroxy macrolide produced by streptomycete strains. Our preliminary researches indicated that it could kill methicillin-resistantStaphylococcus aureus(MRSA) likely by increasing the permeability of cell membrane, and that cell-membrane phospholipids were likely important targets. To confirm this, membrane permeability assay was performed and visualized by fluorescence staining, and then the detailed interactions between azalomycin F5aand model membranes prepared with 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) were determined using attenuated total reflectance fourier transform infrared spectroscopy and31P nuclear magnetic resonance techniques. The results indicated that there were strong interactions between azalomycin F5aand model membranes, especially between azalomycin F5aand the polar head of phospholipid. For further evidence and details, the molecular dynamics (MD) simulation of the interactions between azalomycin F5aand DPPG or lysyl-DPPG were performed using Amber16 software package. A strong interaction between the lactone ring of azalomycin F5aand the polar head of DPPG or lysyl-DPPG had been clearly observed. Moreover, a larger distribution probability out of phospholipid bilayer had been discovered for the guanidyl side chain of azalomycin F5a, especially when probable anion molecules anchoring on the cytoplasmic membrane occurred. Therefore, lipoteichoic acid (LTA), a vital component of gram-positive bacterial envelope, was investigated for its probable interactions with azalomycin F5ausing broth microdilution method. The results showed that azalomycin F5a-induced MRSA lysis could be prevented by LTA. This deduced that there were some interactions between azalomycin F5a, more likely its guanidyl side chain, and LTA. Thereby, azalomycin F5aincreasing the cell-membrane permeability of MRSA had likely achieved by the synergy of its lactone ring binding to the polar head of phospholipid and its guanidyl side chain targeting to LTA, and which had eventually led to the autolysis of MRSA cells.