Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion.
Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion.
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Cfr 介导的抗菌素耐药性的结构基础及其逃避机制。
DOI：
10.1101/2023.09.27.559749
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Polikanov,YuryS
中科院分区：
文献类型：
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作者：
Aleksandrova,ElenaV;Wu,KelvinJY;Tresco,BenIC;Syroegin,EgorA;Killeavy,ErinE;Balasanyants,SamsonM;Svetlov,MaximS;Gregory,StevenT;Atkinson,GemmaC;Myers,AndrewG;Polikanov,YuryS
细菌核糖体是一个基本的药物靶点，因为许多临床上重要的抗生素结合并抑制其功能中心。催化肽转移酶中心(PTC)是几个化学类别中最广泛的抑制剂的靶点。在革兰氏阳性菌中，对PTC作用药物最丰富和临床流行的耐药机制之一是23S核糖体RNA中普遍保守的A2503碱基被CFR甲基酶C8甲基化。尽管它在临床上很重要，但目前对CFR介导的耐药的分子机制缺乏足够的了解。在这里，我们报告了一组CFR修饰的70S核糖体的高分辨结构，其中包含氨基酰基和肽转移RNA。这些结构揭示了在CFR介导的A2503甲基化时核苷酸A2062的变构重排，这可能是导致一些PTC抑制剂效力降低的原因。此外，我们还提供了抗生素伊波沙星和泰乐菌素与CFR甲基化核糖体结合的两种不同机制背后的结构基础。
The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin.