Berberine analog of chloramphenicol exhibits a distinct mode of action and unveils ribosome plasticity

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2024-07-16 DOI:10.1016/j.str.2024.06.013

引用次数: 0

Abstract

Chloramphenicol (CHL) is an antibiotic targeting the peptidyl transferase center in bacterial ribosomes. We synthesized a new analog, CAM-BER, by substituting the dichloroacetyl moiety of CHL with a positively charged aromatic berberine group. CAM-BER suppresses bacterial cell growth, inhibits protein synthesis in vitro, and binds tightly to the 70S ribosome. Crystal structure analysis reveals that the bulky berberine group folds into the P site of the peptidyl transferase center (PTC), where it competes with the formyl-methionine residue of the initiator tRNA. Our toe-printing data confirm that CAM-BER acts as a translation initiation inhibitor in stark contrast to CHL, a translation elongation inhibitor. Moreover, CAM-BER induces a distinct rearrangement of conformationally restrained nucleotide A2059, suggesting that the 23S rRNA plasticity is significantly higher than previously thought. CAM-BER shows potential in avoiding CHL resistance and presents opportunities for developing novel berberine derivatives of CHL through medicinal chemistry exploration.

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氯霉素的小檗碱类似物显示出独特的作用模式并揭示了核糖体的可塑性

氯霉素（CHL）是一种针对细菌核糖体肽基转移酶中心的抗生素。我们用带正电荷的芳香小檗碱基取代 CHL 的二氯乙酰基，合成了一种新的类似物 CAM-BER。CAM-BER 可抑制细菌细胞生长，抑制体外蛋白质合成，并与 70S 核糖体紧密结合。晶体结构分析表明，笨重的小檗碱基团折叠到肽基转移酶中心（PTC）的 P 位点，在那里与启动子 tRNA 的甲酰基蛋氨酸残基竞争。我们的足尖印迹数据证实，CAM-BER 是一种翻译起始抑制剂，与翻译延伸抑制剂 CHL 形成鲜明对比。此外，CAM-BER 还诱导构象受限的核苷酸 A2059 发生明显的重排，这表明 23S rRNA 的可塑性比以前认为的要高得多。CAM-BER 显示出避免 CHL 抗性的潜力，并为通过药物化学探索开发 CHL 的新型小檗碱衍生物提供了机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.