文章基本信息

标题：A long-distance rRNA base pair impacts the ability of macrolide antibiotics to kill bacteria
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作者：Maxim S. Svetlov ; Sophie Cohen ; Nada Alsuhebany 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：4
页码：1971-1975
DOI：10.1073/pnas.1918948117
出版社：The National Academy of Sciences of the United States of America
摘要：While most of the ribosome-targeting antibiotics are bacteriostatic, some members of the macrolide class demonstrate considerable bactericidal activity. We previously showed that an extended alkyl-aryl side chain is the key structural element determining the macrolides’ slow dissociation from the ribosome and likely accounts for the antibiotics’ cidality. In the nontranslating Escherichia coli ribosome, the extended side chain of macrolides interacts with 23S ribosomal RNA (rRNA) nucleotides A752 and U2609, that were proposed to form a base pair. However, the existence of this base pair in the translating ribosome, its possible functional role, and its impact on the binding and cidality of the antibiotic remain unknown. By engineering E. coli cells carrying individual and compensatory mutations at the 752 and 2609 rRNA positions, we show that integrity of the base pair helps to modulate the ribosomal response to regulatory nascent peptides, determines the slow dissociation rate of the extended macrolides from the ribosome, and increases their bactericidal effect. Our findings demonstrate that the ability of antibiotics to kill bacterial cells relies not only on the chemical nature of the inhibitor, but also on structural features of the target.
关键词：ribosome ; antibiotics ; translation ; protein synthesis ; macrolide