Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Nat Prod Rep. 2019 Jan 1;36(1):220-247. doi: 10.1039/c8np00042e. Epub 2018 Jul 6.
Covering: up to 2018Pleuromutilins are a clinically validated class of antibiotics derived from the fungal diterpene (+)-pleuromutilin (1). Pleuromutilins inhibit bacterial protein synthesis by binding to the peptidyl transferase center (PTC) of the ribosome. In this review we summarize the biosynthesis and recent total syntheses of (+)-pleuromutilin (1). We review the mode of interaction of pleuromutilins with the bacterial ribosome, which involves binding of the C14 extension and the tricyclic core to the P and A sites of the PTC, respectively. We provide an overview of existing clinical agents, and discuss the three primary modes of bacterial resistance (mutations in ribosomal protein L3, Cfr methylation, and efflux). Finally we collect structure-activity relationships from publicly available reports, and close with some forward looking statements regarding future development.
截至 2018 年 截短侧耳素是一类经临床验证的抗生素，来源于真菌二萜（+）-截短侧耳素（1）。截短侧耳素通过与核糖体的肽基转移酶中心（PTC）结合来抑制细菌蛋白质合成。在这篇综述中，我们总结了（+）-截短侧耳素（1）的生物合成和最近的全合成。我们综述了截短侧耳素与细菌核糖体的相互作用模式，其中包括 C14 延伸部分和三环核心分别与 PTC 的 P 和 A 位结合。我们概述了现有的临床药物，并讨论了三种主要的细菌耐药模式（核糖体蛋白 L3 的突变、Cfr 甲基化和外排）。最后，我们从公开报告中收集了结构-活性关系，并对未来的发展提出了一些前瞻性的看法。
