Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin
Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin
复制标题
开发针对耐药细菌的等效 Teixobactin 类似物并发现 Lipid II 和 Teixobactin 之间的疏水相互作用
DOI：
10.1021/acs.jmedchem.7b01241
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发表时间：
2018-04-26
影响因子：
7.3
通讯作者：
Rao, Yu
中科院分区：
文献类型：
--
作者：
Zong, Yu;Sun, Xiuyun;Rao, Yu
靶向脂质II的Teixobactin代表了一类具有新颖结构的新型抗生素，对革兰氏阳性病原体具有优异的活性。我们发展了一种新的收敛方法来合成一系列的teixobactin类似物，并探讨了构效关系。我们获得了等效的和简化的teixobactin类似物，用赖氨酸取代L-别-异丙酰亚胺，将苏氨酸上的氧取代为氮，并在D-苯丙氨酸上添加苯基。D-苯丙氨酸的相应修饰导致的抗菌活性的基础上，我们提出了脂质II和teixobactin类似物的N-末端之间的疏水相互作用，我们用我们的类似物35绘制出来。最后，来自我们系列的代表性类似物在肺炎链球菌败血症的小鼠模型中显示出高效率。
Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the L-allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the D-phenylalanine. On the basis of the antibacterial activities that resulted from corresponding modifications of the D-phenylalanine, we propose a hydrophobic interaction between lipid II and the N-terminal of teixobactin analogues, which we map out with our analogue 35. Finally, a representative analogue from our series showed high efficiency in a mouse model of Streptococcus pneumoniae septicemia.