A broad-spectrum lasso peptide antibiotic targeting the bact

发布日期：2025-05-22 10:47 来源：Nature 作者：wshlf 浏览次数：

Lasso peptides (biologically active molecules with a distinct structurally constrained knotted fold) are natural products that belong to the class of ribosomally synthesized and post-translationally modified peptides1,2,3. Lasso peptides act on several bacterial targets4,5, but none have been reported to inhibit the ribosome, one of the main targets of antibiotics in the bacterial cell6,7. Here we report the identification and characterization of the lasso peptide antibiotic lariocidin and its internally cyclized derivative lariocidin B, produced by Paenibacillus sp. M2, which has broad-spectrum activity against a range of bacterial pathogens. We show that lariocidins inhibit bacterial growth by binding to the ribosome and interfering with protein synthesis. Structural, genetic and biochemical data show that lariocidins bind at a unique site in the small ribosomal subunit, where they interact with the 16S ribosomal RNA and aminoacyl-tRNA, inhibiting translocation and inducing miscoding. Lariocidin is unaffected by common resistance mechanisms, has a low propensity for generating spontaneous resistance, shows no toxicity to human cells, and has potent in vivo activity in a mouse model of Acinetobacter baumannii infection. Our identification of ribosome-targeting lasso peptides uncovers new routes towards the discovery of alternative protein-synthesis inhibitors and offers a novel chemical scaffold for the development of much-needed antibacterial drugs.

lasso肽（具有独特结构约束的结状折叠的生物活性分子）是一类核糖体合成并经翻译后修饰的肽。lasso肽能够作用于多种细菌靶标，但尚未有报道表明lasso肽能够抑制细菌细胞中抗生素的主要靶标之一——核糖体。在此，我们报告了lasso肽抗生素lariocidin及其内环化衍生物lariocidin B的鉴定和表征，它们由Paenibacillus sp. M2产生，对多种细菌病原体具有广谱活性。我们发现lariocidin通过结合核糖体并干扰蛋白质合成来抑制细菌生长。结构、遗传和生化数据表明，lariocidin结合在小亚基核糖体的独特位点，与16S核糖体RNA和氨酰tRNA相互作用，抑制易位并诱导误读。lariocidin不受常见耐药机制的影响，产生自发耐药性的倾向低，对人类细胞无毒性，并在小鼠模型中对鲍曼不动杆菌感染显示出强大的体内活性。我们对核糖体靶向lasso肽的鉴定揭示了发现替代蛋白质合成抑制剂的新途径，并为开发急需的抗菌药物提供了一种新的化学框架。

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