Nature nurtures the design of new semi-synthetic macrolide antibiotics.
Nature nurtures the design of new semi-synthetic macrolide antibiotics.
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大自然孕育了新型半合成大环内酯抗生素的设计。
DOI：
10.1038/ja.2016.137
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Pereira D
中科院分区：
文献类型：
--
作者：
Fernandes P;Martens E;Pereira D
红霉素及其类似物用于治疗呼吸道和其他感染。在过去的50年中，这些抗生素的广泛使用导致了世界某些地区20%至70%以上的耐药性。努力寻找对大环内酯类耐药菌株有活性的大环内酯类药物，导致开发了具有烷基-芳基侧链的红霉素类似物，其模拟了16元大环内酯类药物（如泰乐菌素）的糖侧链。通过去除克拉定糖以获得更小的分子，进行了进一步的修饰以提高这些分子的效力，这种修饰是从较老的大环内酯，匹克罗霉素中学习的。在去除克拉定糖后引入酮基以制备新的酮内酯亚类。只有一种酮内酯，泰利霉素，获得了上市许可，但由于严重的不良事件，它不再被广泛使用。由于未能确定导致这种临床毒性的结构关系，导致许多正在开发的酮内酯停药。其中一个完成了临床开发的药物，赛红霉素，不符合临床疗效标准，因此没有获得上市批准。在证明泰利霉素侧链上的咪唑基-吡啶部分对烟碱乙酰胆碱受体的抑制可能是导致严重不良事件的原因后，重新启动了开发新大环内酯类药物的工作。索利霉素是第四代大环内酯，其在2位具有氟，并且具有不同于泰利霉素的烷基-芳基侧链。索利霉素在细菌核糖体上的三个位点上相互作用，对耐旧大环内酯类（包括泰利霉素）的菌株具有活性，并且主要是杀菌的。参与大环内酯类抗生素开发的制药科学家从Satoshi Omura教授的教导中学习，如果没有他的努力，这一领域的进展是不可能的。
Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events. Solithromycin is a fourth-generation macrolide that has a fluorine at the 2-position, and an alkyl-aryl side chain that is different from telithromycin. Solithromycin interacts at three sites on the bacterial ribosome, has activity against strains resistant to older macrolides (including telithromycin), and is mostly bactericidal. Pharmaceutical scientists involved in the development of macrolide antibiotics have learned from the teachings of Professor Satoshi Omura and progress in this field was not possible without his endeavors.
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DOI：
10.3390/antibiotics5030029
发表时间：
2016-09-01
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Jelić D;Antolović R
通讯作者：
Antolović R
影响因子：
3.2
作者：
Berisio, R;Harms, J;Yonath, A
通讯作者：
Yonath, A
影响因子：
4.9
作者：
Gonzalez, Daniel;Palazzi, Debra L.;Cohen-Wolkowiez, Michael
通讯作者：
Cohen-Wolkowiez, Michael
影响因子：
6.1
作者：
Hammerschlag, Margaret R.;Sharma, Roopali
通讯作者：
Sharma, Roopali
影响因子：
4.9
作者：
Kim, So Hyun;Song, Jae-Hoon;Peck, Kyong Ran
通讯作者：
Peck, Kyong Ran