Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
Univ. Bordeaux, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, ARNA, UMR 5320, U1212, Institut Européen de Chimie et Biologie, Pessac, France.
Nat Commun. 2021 Jul 22;12(1):4466. doi: 10.1038/s41467-021-24674-9.
Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.
大环内酯类和酮内酯类抗生素是一类重要的临床抗生素，通过与细菌核糖体的出口通道结合来抑制蛋白质合成。这些抗生素已知在特定序列基序处中断翻译，其中酮内酯类主要在 Arg/Lys-X-Arg/Lys 基序处停滞，而大环内酯类则表现出更广泛的特异性，但它们的上下文特异性作用的结构基础一直缺乏。在这里，我们展示了在由大环内酯类红霉素（ERY）和酮内酯类泰利霉素（TEL）合成 Arg-Leu-Arg 序列过程中核糖体被捕获的结构。与深度诱变和分子动力学模拟一起，这些结构揭示了 ERY 和 TEL 如何与 Arg-Leu-Arg 基序相互作用以诱导翻译停滞，并阐明了 ERY 比 TEL 具有较弱的序列特异性作用的基础。由于 Arg/Lys-X-Arg/Lys 基序的程序性停滞被用于激活抗生素耐药基因的表达，因此我们的研究还为未来开发改良的大环内酯类抗生素提供了重要的见解。
