The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria
The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria
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DOI：
10.1016/j.molcel.2007.04.005
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发表时间：
2007-05-11
期刊：
影响因子：
16
通讯作者：
Mankin, Alexander S.
中科院分区：
文献类型：
--
作者：
Leach, Karen L.;Swaney, Steven M.;Mankin, Alexander S.
恶唑烷酮类抗生素是一类最新的抗生素。它们通过干扰蛋白质的合成来抑制细菌的生长。恶唑烷酮的作用机制和药物结合部位在核糖体中的准确位置尚不清楚。我们使用一组光反应衍生物来确定恶唑烷酮类化合物在细菌和人类细胞核糖体中的作用部位。体内的交联数据被用来模拟恶唑烷酮分子在其在肽基转移酶中心(PTC)的结合位置。恶唑烷酮与细菌核糖体的A位相互作用，在那里它们应该干扰氨基酰-tRNA的放置。在人类细胞中，恶唑烷酮类化合物与线粒体核糖体的PTC中的rRNA发生交联，而不是细胞质核糖体中的rRNA。恶唑烷酮与线粒体核糖体的相互作用为线粒体蛋白质合成的抑制提供了结构基础，这与恶唑烷酮治疗相关的临床副作用有关。
The oxazolidinones are one of the newest classes of antibiotics. They inhibit bacterial growth by interfering with protein synthesis. The mechanism of oxazolidinone action and the precise location of the drug binding site in the ribosome are unknown. We used a panel of photoreactive derivatives to identify the site of action of oxazolidinones in the ribosomes of bacterial and human cells. The in vivo crosslinking data were used to model the position of the oxazolidinone molecule within its binding site in the peptidyl transferase center (PTC). Oxazolidinones interact with the A site of the bacterial ribosome where they should interfere with the placement of the aminoacyl-tRNA. In human cells, oxazolidinones were crosslinked to rRNA in the PTC of mitochondrial, but not cytoplasmic, ribosomes. Interaction of oxazolidinones with the mitochondrial ribosomes provides a structural basis for the inhibition of mitochondrial protein synthesis, which is linked to clinical side effects associated with oxazolidinone therapy.