The general mode of translation inhibition by macrolide antibiotics
The general mode of translation inhibition by macrolide antibiotics
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DOI：
10.1073/pnas.1417334111
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发表时间：
2014-11-11
影响因子：
11.1
通讯作者：
Mankin, Alexander S.
中科院分区：
文献类型：
--
作者：
Kannan, Krishna;Kanabar, Pinal;Mankin, Alexander S.
大环内酯类是临床上重要的抗生素，被认为通过阻碍新合成的多肽通过细菌核糖体的新生肽出口通道来抑制细菌生长。最近的数据挑战了这一观点，表明大环内酯类抗生素可以差异影响个别蛋白质的合成。为了了解大环内酯类作用的一般机制，我们使用全基因组核糖体分析，并分析了用高浓度大环内酯类抗生素处理的细菌细胞中翻译高表达基因的核糖体的再分布。元基因分析表明，早期几轮翻译的抑制，这将是大环内酯类药物作用的传统观点的特征，只发生在有限数量的基因。大多数基因的翻译都是通过5 '端密码子进行的，当核糖体遇到特定的短序列基序时，可以在更远端的密码子处停止。有问题的序列基序局限于肽基转移酶中心的新生肽残基，但不限于在出口通道中接触抗生素分子的肽段。因此，似乎大环内酯作用的一般模式涉及选择性抑制供体和受体底物的特定组合之间的肽键形成。在活细胞中起作用但在体外蛋白质合成过程中不起作用的其他因素可能调节大环内酯类抗生素的位点特异性作用。
Macrolides are clinically important antibiotics thought to inhibit bacterial growth by impeding the passage of newly synthesized polypeptides through the nascent peptide exit tunnel of the bacterial ribosome. Recent data challenged this view by showing that macrolide antibiotics can differentially affect synthesis of individual proteins. To understand the general mechanism of macrolide action, we used genome-wide ribosome profiling and analyzed the redistribution of ribosomes translating highly expressed genes in bacterial cells treated with high concentrations of macrolide antibiotics. The metagene analysis indicated that inhibition of early rounds of translation, which would be characteristic of the conventional view of macrolide action, occurs only at a limited number of genes. Translation of most genes proceeds past the 5'-proximal codons and can be arrested at more distal codons when the ribosome encounters specific short sequence motifs. The problematic sequence motifs are confined to the nascent peptide residues in the peptidyl transferase center but not to the peptide segment that contacts the antibiotic molecule in the exit tunnel. Therefore, it appears that the general mode of macrolide action involves selective inhibition of peptide bond formation between specific combinations of donor and acceptor substrates. Additional factors operating in the living cell but not functioning during in vitro protein synthesis may modulate site-specific action of macrolide antibiotics.