【作者】 郑忠辉；

【导师】 刘浚； 宋丹青；

【作者基本信息】 中国协和医科大学 ， 微生物与生化药学， 2005， 博士

【摘要】 近年来，抗生素和抗菌剂的耐药菌迅速增多，如耐甲氧西林金黄色葡萄球菌(MRSA)、耐甲氧西林表皮葡萄球菌(MRPA)、 耐青霉类肺炎链球菌(PRSP)、耐万古霉素的肠球菌(VIlE)、超广谱β-内酰胺酶(ESBL)、AmPC酶与金属β-内酰胺酶(MBL)产生菌等的出现，给临床细菌性感染治疗带来很大的困难。肺炎链球菌的耐药性也以惊人的速度在增长，更为严重的是临床多种抗生素的大量使用，导致多重耐药问题出现，青霉素、大环内酯类、甲氧苄胺嘧啶-磺胺甲基异噁唑、四环素类、氟喹诺酮和氯霉素等耐药及多重耐药的肺炎链球菌社区获得性呼吸道感染(CA-RTIS)逐年呈上升趋势，β-内酰胺耐药的嗜血流杆菌、卡他莫拉菌、耐甲氧西林金黄色葡萄球菌(MRSA)的感染日益成为一个临床难题。未来几十年里，许多抗生素可能因耐药而大幅减效。因而，加快新结构的抗生素的研究，是医药科研工作者的紧迫任务。 红霉素类药物作为临床一线用药，其优越性相当明显，成本低、口服方便、抗菌谱广、体内组织分布好、组织浓度高，从1950′s开始，广泛应用于临床，在社区获得性呼吸道感染、皮肤及软组织感染的治疗发挥了重要作用。二十世纪80年代开始，红霉素的研究工作进入了复兴时期，尤其是针对改善其副作用、增加对酸稳定性、减少胃肠道刺激、增加组织浓度、延长半衰期等方面作了大量的工作，已经合成并在临床实践中得到了为数不少的有价值的侯选药物和治疗药物，如罗红霉素、克拉霉素、阿奇霉素、地红霉素等。由于大环内酯类抗生素独特的疗效，在此领域进行深入的研究，成为当前热点之一。 Cethromycin(赛红霉素，ABT-773)是全新结构的第三代大环内酯类抗生素，如同泰利霉素，C-3位具有羰基结构，被成为酮内酯型抗生素。其主要的作用机制是与细菌50S核糖体亚单位的23sRNA的V结构域结合，促进转录阶段肽的早熟性解离，抑制细菌蛋白质的合成。对大环内酯类抗生素敏感性、耐药性呼吸道致病菌如肺炎链球菌、黏膜炎莫拉氏菌、金黄色葡萄球菌、流感嗜血菌、酿脓链球菌、肺炎支原体和嗜肺军团菌等有很强的抑制活性，良好的生化特性及药代动力学性质，毒性小，有望成为新一代大环内酯抗生素。 设计了三条合成路线，其中两条路线成功地合成了赛红霉素。第一条是以文献方法为基础，对反应进行了工艺改进；第二种方法未获成功，却提供了有价值的指导，为今后对此工艺进行深入的研究打下了基础；第三种方法，吸收了Heck更多还原

【Abstract】 The rapid development of antibioitics -resistant strains such as MRSA MRPA PRSP VRE ESBL AMPC MBL have caused difficulty to clinical treatment in recent years. As one of common bacterial species, Streptococccus Peumoniae is growing in a trans-normal rapidity, moreover the abuse of antibioitics in clinic caused muti-drugs resistance. Bacterial community-acquired respiratory tract infections (CA-RTS) caused by resistant or muti-drugs resistant S. Peumoniae, various pattern of penicillins, amcrolides, trimethoprim—sufamethoxazole, tetracycline, furoquinolone and chloramphenicol resistant isolates is prevailing, the infections in clinical associated with β-lactam resistance in H.influenzae and M.catarrrhalis, muti-drugs resistant methiciliin -resistant Straphylococcus Aureas is also becoming a serious clinical problem. Many antibiotics or antibacterial-drugs many decrease the efficacy in a high dgree, thus, all the pharmaceutists are seeking new antibiotics which have new structure.Erythromycin as a standing macrolide antibacterial drug has notable advantages such as low consume, broad antibacterial spectrum, pharmaceutical activities and oral adminstration, has been used in clinically sine 1950s, it applys to treatment of community-acquired respiratory of the respiratory tract and skin or soft tissues infections, up to date, it remains the reference of the macrolides. Outstanding development has been obtained in macrolides of erythromycin derivatives from 1980s, some studies were carried through to decrease the side -effects and to increase the acid stability, and the bio-availability, reduce the gastrointestinal side effects, and several valuable new drugs or compounds in the practice of clinic, Rexithromycin, Clathromycin, Azithromycin and Dithromycin came into the market successfully. Since their unique therapy efficacy, research in the domain of macrolides becomes the most active point.Cethromycin (ABT-773) is a novel structure macrolide, like Telithromycin. Named ketolide for it derived from 14-memberd-ring macrolide and being characterized by a carbonyl group at the C-3 position. It inhibit bacterial protein synthesis by bang to the 50s ribosomal subunit in domain V of the 23SrRNA and causing premature dissociation更多还原