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A long-distance rRNA base pair impacts the ability of macrolide antibiotics to kill bacteria.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-01-13 , DOI: 10.1073/pnas.1918948117
Maxim S Svetlov 1 , Sophie Cohen 1 , Nada Alsuhebany 1 , Nora Vázquez-Laslop 1 , Alexander S Mankin 2
Affiliation  

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.

中文翻译:

长距离rRNA碱基对影响大环内酯类抗生素杀死细菌的能力。

虽然大多数靶向核糖体的抗生素具有抑菌作用,但大环内酯类药物中的某些成员具有相当大的杀菌活性。我们以前表明,延长的烷​​基-芳基侧链是决定大环内酯类药物从核糖体缓慢解离的关键结构要素,并可能解释了抗生素的流行性。在非翻译大肠杆菌核糖体中,大环内酯类化合物的延伸侧链与23S核糖体RNA(rRNA)核苷酸A752和U2609相互作用,后者被提议形成碱基对。然而,该碱基对在翻译核糖体中的存在,其可能的功能作用及其对抗生素的结合和抑制作用的影响仍然未知。通过改造在752和2609 rRNA位置携带单个和补偿性突变的大肠杆菌细胞,我们表明,碱基对的完整性有助于调节核糖体对调节性新生肽的应答,决定了延伸的大环内酯类药物从核糖体的缓慢解离速率,并增加了其杀菌作用。我们的发现表明,抗生素杀死细菌细胞的能力不仅取决于抑制剂的化学性质,还取决于靶标的结构特征。
更新日期:2020-01-29
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