Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics.
Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics.
复制标题
DOI：
10.1021/acs.accounts.0c00894
复制
发表时间：
2021-04-20
影响因子：
18.3
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Cai L;Seiple IB;Li Q
抗生素耐药性的持续、快速发展已成为全球性的健康危机和全球经济的负担。需要采取果断和全面的行动来减缓抗生素耐药性的传播，包括增加对抗生素发现的投资，为新推出的抗生素提供投资回报的可持续政策，以及减少抗生素过度使用的公共教育，特别是在畜牧业和农业中。如果不对目前的抗生素管道进行重大改变，我们就有可能进入后抗生素时代。在这个帐户中，我们总结了我们最近的努力，开发下一代链阳菌素和兰卡菌素抗生素，克服细菌耐药性的模块化化学合成的手段。首先，我们描述了我们的高度模块化，可扩展的路线，从7个简单的化学构建模块，在6-8个步骤中获得4种天然A组链阳性菌素抗生素。接下来，我们描述了应用这种途径合成一种新的链阳性菌素抗生素库，通过体外和体内生物学评价和高分辨率冷冻电子显微镜观察。一种先导化合物在体外和体内对一种长期存在的链阳菌素耐药机制维吉尼亚霉素乙酰转移酶表现出优异的抑制活性。我们的研究结果表明，合理设计和模块化化学合成的结合可以振兴类抗生素，是有限的自然产生的耐药性机制。其次，我们叙述了我们对lankacidin抗生素的模块化方法。Lankacidins是一组聚酮化合物天然产物，具有抗几种革兰氏阳性菌菌株的活性，但由于其化学不稳定性而尚未用作治疗剂。我们描述了从简单结构单元以≤ 8步的线性序列获得2，18-断链-羊毛脂酸醇B的几种非对映体的路线，从而对C4立体化学进行了修订。接下来，我们详细介绍了我们的模块化合成的几个非对映异构体的iso-lankacidinol，导致这种天然产物的结构重新分配。这些结构的修订提出了有趣的问题，生物合成的起源lankacidins，所有这些都具有统一的立体化学之前，这些发现。最后，我们总结了几个iso-和seco-lankacidins抑制细菌生长和抑制体外翻译的能力，为该类的结构-功能关系提供了重要的见解。
Continued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive and comprehensive action is required to slow down the spread of antibiotic resistance, including increased investment in antibiotic discovery, sustainable policies that provide returns on investment for newly launched antibiotics, and public education to reduce the over usage of antibiotics, especially in livestock and agriculture. Without significant changes in the current antibiotic pipeline, we are in danger of entering a post-antibiotic era. In this account, we summarize our recent efforts to develop next-generation streptogramin and lankacidin antibiotics that overcome bacterial resistance by means of modular chemical synthesis. First, we describe our highly modular, scalable route to four natural group A streptogramins antibiotics in 6-8 steps from seven simple chemical building blocks. We next describe the application of this route to the synthesis of a novel library of streptogramin antibiotics informed by in vitro and in vivo biological evaluation and high-resolution cryo-electron microscopy. One lead compound showed excellent inhibitory activity in vitro and in vivo against a longstanding streptogramin-resistance mechanism, virginiamycin acetyltransferase. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. Second, we recount our modular approaches toward lankacidin antibiotics. Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria, but have not been deployed as therapeutics due to their chemical instability. We describe a route to several diastereomers of 2,18-seco-lankacidinol B in a linear sequence of ≤ 8 steps from simple building blocks, resulting in a revision of the C4 stereochemistry. We next detail our modular synthesis of several diastereoisomers of iso-lankacidinol that resulted in the structural reassignment of this natural product. These structural revisions raise interesting questions about the biosynthetic origin of lankacidins, all of which possessed uniform stereochemistry prior to these finding. Finally, we summarize the ability of several iso- and seco-lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro, providing important insights into structure-function relationships for the class.
登录
查看更多内容
影响因子：
3.3
作者：
Lu, Chang;Li, Jin-Meng;Wang, Xiang-Jing
通讯作者：
Wang, Xiang-Jing
影响因子：
15
作者：
Cai L;Yao Y;Yeon SK;Seiple IB
通讯作者：
Seiple IB
DOI：
10.1039/p19850002763
发表时间：
1985-12-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
影响因子：
--
作者：
FRAY, MJ;THOMAS, EJ;WILLIAMS, DJ
通讯作者：
WILLIAMS, DJ
DOI：
10.1039/c39790001180
发表时间：
1979-01-01
影响因子：
--
作者：
DEVOS, A;REMION, J;GHOSEZ, L
通讯作者：
GHOSEZ, L
影响因子：
2.1
作者：
Li, Qi;Seiple, Ian B.
通讯作者：
Seiple, Ian B.