麦克马斯特大学Gerard D. Wright研究小组取得一项新突破。他们报道了一种针对细菌核糖体的广谱套索肽抗生素。这一研究成果于2025年3月26日发表在国际顶尖学术期刊《自然》上。

本文报道了套索肽抗生素lariocidin及其内环衍生物lariocidin B的鉴定和特性。M2对一系列细菌病原体具有广谱活性。研究人员发现，落叶松素通过与核糖体结合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，lariocidins结合在小核糖体亚基的一个独特位点，在那里它们与16S核糖体RNA和氨基酰基tRNA相互作用，抑制易位并诱导错误编码。Lariocidin不受常见耐药机制的影响，产生自发耐药的倾向较低，对人体细胞没有毒性，并且在鲍曼不动杆菌感染的单主题模型中具有强大的体内活性。他们对核糖体靶向套索肽的鉴定为发现替代蛋白质合成抑制剂开辟了新的途径，并为开发急需的抗菌药物提供了新的化学支架。

据介绍，Lasso肽（具有独特结构约束的生物活性分子）是核糖体合成和翻译后修饰肽类的天然产物。Lasso肽作用于几种细菌靶点，但没有报道能抑制核糖体，而核糖体是细菌细胞中抗生素的主要靶点之一。

附：英文原文

Title: A broad-spectrum lasso peptide antibiotic targeting the bacterial ribosome

Author: Jangra, Manoj, Travin, Dmitrii Y., Aleksandrova, Elena V., Kaur, Manpreet, Darwish, Lena, Koteva, Kalinka, Klepacki, Dorota, Wang, Wenliang, Tiffany, Maya, Sokaribo, Akosiererem, Coombes, Brian K., Vzquez-Laslop, Nora, Polikanov, Yury S., Mankin, Alexander S., Wright, Gerard D.

Issue&Volume: 2025-03-26

Abstract: 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.

DOI: 10.1038/s41586-025-08723-7

Source: https://www.nature.com/articles/s41586-025-08723-7