【作者】 王其蕊；

【导师】 马淑涛；

【作者基本信息】 山东大学 ， 药物化学， 2006， 硕士

【摘要】 从上个世纪五十年代大环内酯开始应用于临床以来，到现在已有近六十年的历史，而且大环内酯类抗生素一直在抗感染领域发挥着重要作用。但是，随着抗生素的广泛应用，特别是持续、不当使用，在临床上出现了严重的耐药问题，耐药性产生的直接后果是严重影响临床疗效，甚至导致治疗失败。 大环内酯类抗生素的作用机制是与细菌核糖体50S亚基上的23S rRNA结合，从而抑制蛋白质的合成来发挥抗菌活性，其具体结合部位是Ⅴ区的A2058靶点。而细菌对大环内酯的主要耐药机制是靶点修饰：耐药基因erm编码的甲基转移酶对A2058上的N~6进行甲基化，使这一靶点不能与大环内酯抗生素结合，从而赋予细菌耐药性。 为了改善大环内酯类抗生素对耐药菌的抗菌活性，人们对其结构进行了修饰得到了大量衍生物，其中最有成就的是酮内酯抗生素。它不仅能通过5-位去氧氨基糖与Ⅴ区的A2058靶点，而且还可通过侧链与Ⅱ区的A752结合，从而发挥抗耐药菌活性。 最新的研究表明，细菌核糖体50S亚基上的很多区域能与大环内酯类抗生素结合，人们将这些能与大环内酯类抗生素结合区域称之为“口袋”。现代核糖体-大环内酯结构结晶学研究表明大环内酯抗生素3-位克拉定糖位于肽基转移酶中心，临近肽基转移酶通道出口处的A2610和A2655。因此，以A2610或A2655为靶点，在大环内酯抗生素3-位克拉定糖或3-位羟基上引入侧链，侧链的末端连接着对靶点亲和力强的基团，以便能与肽基转移酶通道出口的A2610或A2655更多还原

【Abstract】 Macrolide antibiotics have been widely used for the treatment of bacterial infections for nearly sixty years since the early 1950s and have been playing an important role in the clinic. With the extensive use of the antibiotics, especially abuse, the serious problem of bacterial resistance has happened in the clinic, which results in a decrease in curative effect, and even no effect.The macrolides’ mechanism of action is that they can bind to the target of A2058 in domain Vof the 23S rRNA in 50S subunit of bacterial ribosome and exert their antibacterial activities by inhibiting protein synthesis of bacteria. However, the main mechanism of the bacterial resistance to macrolides is the modification of the target, the methylation of N~6 on A2058 by peptidyl transferase coded by gene erm, which makes the target not to bind to macrolides. Consequently, the bacterial resistance appears.In order to enhance the activities of macrolides against resistant bacteria, a great number of macrolide derivatives have been synthesized through the structural modification. Among them, the best successful example is ketolides which produce not only the potent antibacterial activities by binding to the target of A2058 in domain V through 5-desosamine, but also the strong activities against resistant bacteria by binding to the target of A752 through their side chains.更多还原