Structural Characterization of an Alternative Mode of Tigecycline Binding to the Bacterial Ribosome
Structural Characterization of an Alternative Mode of Tigecycline Binding to the Bacterial Ribosome
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DOI：
10.1128/aac.04895-14
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发表时间：
2015-05-01
影响因子：
4.9
通讯作者：
Fucini, Paola
中科院分区：
文献类型：
--
作者：
Schedlbauer, Andreas;Kaminishi, Tatsuya;Fucini, Paola
尽管四环素和替加环素均通过空间阻碍tRNA与核糖体A位点的结合来抑制蛋白质合成，但替加环素在体外和体内活性测定中均显示出增加的功效，并且避免了与四环素类抗生素相关的最常见的耐药机制。这些活性差异归因于替加环素中发现的叔丁基甘氨酰氨基侧链。我们通过X射线晶体学进行的结构分析表明，替加环素结合细菌30S核糖体亚基，其尾部呈延伸构象，并与16S rRNA核苷酸C1054发生广泛的相互作用。这些相互作用限制了C1054的移动性，并有助于替加环素的抗微生物活性，包括其对核糖体保护蛋白的抗性。
Although both tetracycline and tigecycline inhibit protein synthesis by sterically hindering the binding of tRNA to the ribosomal A site, tigecycline shows increased efficacy in both in vitro and in vivo activity assays and escapes the most common resistance mechanisms associated with the tetracycline class of antibiotics. These differences in activities are attributed to the tert-butylglycylamido side chain found in tigecycline. Our structural analysis by X-ray crystallography shows that tigecycline binds the bacterial 30S ribosomal subunit with its tail in an extended conformation and makes extensive interactions with the 16S rRNA nucleotide C1054. These interactions restrict the mobility of C1054 and contribute to the antimicrobial activity of tigecycline, including its resistance to the ribosomal protection proteins.