研究提出了一种天然的沉积肽抗生素结合细菌核糖体的E位点
麦克马斯特大学Gerard D. Wright小组近日取得一项新成果。经过不懈努力，他们的最新研究提出了一种天然的沉积肽抗生素结合细菌核糖体的E位点。相关论文于2026年6月3日发表于国际顶尖学术期刊《自然》杂志上。
在这里，该课题组证明了通过改进的分离方法，丰富了以前被忽视的次要产物，即使是经过充分研究的产生抗生素的放线菌菌株也可以提供具有独特作用模式的新化学支架。通过从土壤细菌中分离出天然产物提取物，该课题组人员发现链霉菌（Streptomyces rimothem），即众所周知的抗生素土霉素（oxy四环素）的来源，产生一种环状沉积肽抗生素，该课题组人员称之为马可霉素（manikomycin）。马可霉素可以杀死多重耐药肠杆菌科，不受临床主题抗生素相关耐药的影响。生化、遗传和结构分析表明，马可霉素结合在细菌核糖体大亚基的E位点，阻止tRNA的3端进入E位点，并以序列-上下文特异性的方式有效地阻碍蛋白质合成的易位步骤。据他们所知，马可霉素是第一种针对核糖体大亚基中关键但未被充分开发的E位点的抗菌剂，突出了其作为开发新抗生素的先导物的价值。
研究人员表示，解决抗生素耐药性危机的一个关键挑战是确定新的抗微生物化合物。虽然真菌和细菌，特别是放线菌产生的天然产物是过去80年来发现的大多数抗生素的来源，但由于已知药物支架的频繁重新发现，它们已经不再受欢迎。目前的看法是，产生抗生素的放线菌已被过度开采，几乎没有新颖性。
附：英文原文
Title: A natural depsipeptide antibiotic binds the E-site of the bacterial ribosome
Author: Kaur, Manpreet, Travin, Dmitrii Y., Berger, Max J., Jangra, Manoj, Morici, Martino, Safdari, Haaris A., Klepacki, Dorota, Wang, Wenliang, Cook, Michael, Chou, Sommer, Guitor, Allison K., Koteva, Kalinka, Xu, Min, Ejim, Linda, Fiebig, Aline, Yousefi, Yeganeh, Coombes, Brian K., Macneil, Lesley, Vzquez-Laslop, Nora, Mankin, Alexander S., Wilson, Daniel N., Wright, Gerard D.
Issue&Volume: 2026-06-03
Abstract: A key challenge in addressing the antibiotic resistance crisis is identifying new antimicrobial compounds1. Although natural products produced by fungi and bacteria, particularly actinomycetes, have been the source of most antibiotics discovered over the past 80 years, they have fallen out of favour owing to the frequent rediscovery of known drug scaffolds2. The current perception is that antibiotic-producing actinomycetes have been over-mined and possess little novelty left to yield. Here we demonstrate that by using improved fractionation approaches that enrich previously overlooked minor products, even well-studied strains of antibiotic-producing actinomycetes can provide new chemical scaffolds with unique modes of action. By fractionating a library of natural product extracts from soil bacteria, we show that Streptomyces rimosus, the source of the well-known antibiotic oxytetracycline, produces a cyclic depsipeptide antibiotic that we call manikomycin. Manikomycin can kill multidrug-resistant Enterobacteriaceae and is not susceptible to resistance associated with clinically used antibiotics. Biochemical, genetic and structural analyses reveal that manikomycin binds in the E-site of the large subunit of the bacterial ribosome, preventing entry of the 3′ end of the tRNA into the E-site and effectively hindering the translocation step of protein synthesis in a sequence-context-specific manner. Manikomycin is the first antibacterial agent, to our knowledge, to target the critical but underexplored E-site in the large ribosomal subunit, highlighting its value as a lead for developing new antibiotics.
DOI: 10.1038/s41586-026-10589-2
Source: https://www.nature.com/articles/s41586-026-10589-2
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
投稿链接：http://www.nature.com/authors/submit_manuscript.html
