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

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Berberine analog of chloramphenicol exhibits a distinct mode of action and unveils ribosome plasticity
Structure ( IF 4.4 ) Pub Date : 2024-07-16 , DOI: 10.1016/j.str.2024.06.013
Zahra Batool ₁ , Julia A Pavlova ₂ , Madhura N Paranjpe ₁ , Andrey G Tereshchenkov ₂ , Dmitrii A Lukianov ₃ , Ilya A Osterman ₃ , Alexey A Bogdanov ₄ , Natalia V Sumbatyan ₃ , Yury S Polikanov ₅

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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.

中文翻译：

氯霉素的小檗碱类似物表现出独特的作用模式并揭示核糖体可塑性

氯霉素 (CHL) 是一种针对细菌核糖体中肽基转移酶中心的抗生素。我们通过用带正电荷的芳香小檗碱基团取代 CHL 的二氯乙酰基部分，合成了一种新的类似物 CAM-BER。 CAM-BER 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，庞大的小檗碱基团折叠到肽基转移酶中心 (PTC) 的 P 位点，与起始 tRNA 的甲酰基蛋氨酸残基竞争。我们的脚趾打印数据证实，CAM-BER 作为翻译起始抑制剂，与 CHL（翻译延伸抑制剂）形成鲜明对比。此外，CAM-BER 诱导构象限制的核苷酸 A2059 发生明显的重排，表明 23S rRNA 的可塑性明显高于之前认为的。 CAM-BER 显示出避免 CHL 耐药性的潜力，并为通过药物化学探索开发新型 CHL 小檗碱衍生物提供了机会。

更新日期：2024-07-16

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