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首页> 外文期刊>Journal of bacteriology >Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA
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Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA

机译：大环内酯类抗生素在核糖体上的结合位点：新的抗性突变确定了ketolides与rRNA的特定相互作用。

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Macrolides represent a clinically important class of antibiotics that block protein synthesis by interacting with the large ribosomal subunit. The macrolide binding site is composed primarily of rRNA. However, the mode of interaction of macrolides with rRNA and the exact location of the drug binding site have yet to be described. A new class of macrolide antibiotics, known as ketolides, show improved activity against organisms that have developed resistance to previously used macrolides. The biochemical reasons for increased potency of ketolides remain unknown. Here we describe the first mutation that confers resistance to ketolide antibiotics while leaving cells sensitive to other types of macrolides. A transition of U to C at position 2609 of 23S rRNA rendered E. coli cells resistant to two different types of ketolides, telithromycin and ABT-773, but increased slightly the sensitivity to erythromycin, azithromycin, and a cladinose-containing derivative of telithromycin. Ribosomes isolated from the mutant cells had reduced affinity for ketolides, while their affinity for erythromycin was not diminished. Possible direct interaction of ketolides with position 2609 in 23S rRNA was further confirmed by RNA footprinting. The newly isolated ketolide-resistance mutation, as well as 23S rRNA positions shown previously to be involved in interaction with macrolide antibiotics, have been modeled in the crystallographic structure of the large ribosomal subunit. The location of the macrolide binding site in the nascent peptide exit tunnel at some distance from the peptidyl transferase center agrees with the proposed model of macrolide inhibitory action and explains the dominant nature of macrolide resistance mutations. Spatial separation of the rRNA residues involved in universal contacts with macrolides from those believed to participate in structure-specific interactions with ketolides provides the structural basis for the improved activity of the broader spectrum group of macrolide antibiotics.
机译：大环内酯类药物是临床上重要的一类抗生素，可通过与大核糖体亚基相互作用来阻止蛋白质合成。大环内酯结合位点主要由rRNA组成。但是，大环内酯类药物与rRNA的相互作用方式以及药物结合位点的确切位置尚待描述。一类新的大环内酯类抗生素，称为酮醇内酯，对已对以前使用的大环内酯类产生抗药性的生物体显示出增强的活性。酮醇化物效力增加的生化原因仍然未知。在这里，我们描述了第一个突变，赋予了对酮内酯抗生素的抗性，同时使细胞对其他类型的大环内酯类药物敏感。在23S rRNA的2609位置U到C的过渡变成了E。大肠杆菌细胞对两种不同类型的酮醚泰特罗霉素和ABT-773具有抗性，但对红霉素，阿奇霉素和含克雷德糖的泰利斯霉素衍生物的敏感性稍有提高。从突变细胞中分离出的核糖体对酮类的亲和力降低，而对红霉素的亲和力却没有降低。 RNA足迹进一步证实了酮缩酮与23S rRNA中2609位的可能直接相互作用。在大核糖体亚基的晶体结构中，对新分离出的酮内酯抗性突变以及先前显示的与大环内酯类抗生素相互作用涉及的23S rRNA位置进行了建模。大环内酯结合位点在新生肽出口通道中距肽基转移酶中心一定距离的位置与拟议的大环内酯抑制作用模型相符，并解释了大环内酯抗性突变的显性。与大环内酯类药物普遍接触所涉及的rRNA残基与据信参与与酮醇化物的结构特异性相互作用的那些rRNA残基的空间分离，为大环内酯类抗生素广谱组的活性改善提供了结构基础。

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