Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Katholieke Universiteit Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
Eur J Med Chem. 2011 Nov;46(11):5227-36. doi: 10.1016/j.ejmech.2011.08.049. Epub 2011 Sep 16.
Increasing resistance to antibiotics is a major problem worldwide and provides the stimulus for development of new bacterial inhibitors with preferably different modes of action. In search for new leads, several new bacterial targets are being exploited beside the use of traditional screening methods. Hereto, inhibition of bacterial protein synthesis is a long-standing validated target. Aminoacyl-tRNA synthetases (aaRSs) play an indispensable role in protein synthesis and their structures proved quite conserved in prokaryotes and eukaryotes. However, some divergence has occurred allowing the development of selective aaRS inhibitors. Following an outline on the action mechanism of aaRSs, an overview will be given of already existing aaRS inhibitors, which are largely based on mimics of the aminoacyl-adenylates, the natural reaction intermediates. This is followed by a discussion on more recent developments in the field and the bioavailability problem.
抗生素耐药性的增加是一个全球性的主要问题，这为开发具有不同作用机制的新型细菌抑制剂提供了动力。在寻找新的先导化合物时，除了使用传统的筛选方法外，还在利用几种新的细菌靶点。为此，抑制细菌蛋白质合成是一个长期以来得到验证的目标。氨酰-tRNA 合成酶（aaRSs）在蛋白质合成中起着不可或缺的作用，它们的结构在原核生物和真核生物中被证明是相当保守的。然而，一些分歧的出现使得选择性 aaRS 抑制剂得以发展。在概述了 aaRSs 的作用机制之后，将概述现有的 aaRS 抑制剂，这些抑制剂主要基于氨酰-腺苷酸的类似物，即天然的反应中间体。接下来将讨论该领域的最新进展和生物利用度问题。
