Structural Basis for Linezolid Binding Site Rearrangement in the Staphylococcus aureus Ribosome
Structural Basis for Linezolid Binding Site Rearrangement in the Staphylococcus aureus Ribosome
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DOI：
10.1128/mbio.00395-17
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发表时间：
2017-05-01
期刊：
影响因子：
6.4
通讯作者：
Yonath, Ada
中科院分区：
文献类型：
--
作者：
Belousoff, Matthew J.;Eyal, Zohar;Yonath, Ada
通过冷冻电子显微镜（cryo-EM）在金黄色葡萄球菌临床分离株的70 S核糖体中发现了对抗生素利奈唑胺的非正统、令人惊讶的耐药机制。该高分辨率结构信息表明，核糖体蛋白uL 3中的单个氨基酸缺失赋予利奈唑胺耐药性，尽管其位于肽基转移酶中心距离利奈唑胺结合口袋24埃处。这种突变会诱导rRNA的一系列变构结构重排，最终导致抗生素结合位点的改变。重要信息各种抗生素耐药突变对人类健康造成的日益沉重的负担现在包括流行的金黄色葡萄球菌对最后一线抗菌药物如利奈唑胺和达托霉素的耐药性。结构知情的药物修饰代表了设计先进临床疗法的前沿，但这一策略的成功需要快速，简便的方法来阐明耐药性的结构基础（D. Brown，Nat Rev Drug Discov 14：821-832，2015，https：//doi.org/10.1038/nrd4675）。在这里，详细的结构信息表明，一种常见的机制在利奈唑胺耐药性中起作用，并为重新设计恶唑烷酮抗生素提供了一个步骤，这是一种可以挫败利奈唑胺耐药性已知机制的策略。
An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus. This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 angstrom away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site.IMPORTANCE The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent Staphylococcus aureus resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821-832, 2015, https://doi.org/10.1038/nrd4675). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance.