Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosomes by interfering with translation elongation. Structural analysis of the ribosome–KLB complex showed that the compound binds in the peptide exit tunnel overlapping with the binding sites of macrolides or streptogramin-B. KLB adopts a compact conformation and largely obstructs the tunnel. Engineered KLB fragments were observed to retain in vitro activity, and thus have the potential to serve as a starting point for the development of new bioactive compounds.

中文翻译：

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Klebsazolicin通过阻止肽出口通道抑制70S核糖体

筛选大多数可培养微生物产生的小分子代谢物通常会导致已知化合物的重新发现，而基因组挖掘程序使研究人员能够利用更大的化学多样性，并发现新的分子支架。在这里，我们报告了一种新的抗生素，从肺炎克雷伯氏菌（Klebsiella pneumoniae）的新抗生素，klebsazolicin（KLB）的基因组指导下的鉴定，该酶通过靶向核糖体来抑制敏感细胞的生长。核糖体合成的翻译后修饰肽（RiPP）KLB的特征是存在一个对其活性至关重要的独特N末端ring环。体外生化研究表明，KLB通过干扰翻译延伸来抑制核糖体。核糖体-KLB复合物的结构分析表明，该化合物在肽出口通道中结合，与大环内酯或链霉菌素-B的结合位点重叠。KLB采用紧凑的构造，并在很大程度上阻塞了隧道。观察到工程化的KLB片段保留了体外活性，因此具有作为开发新的生物活性化合物的起点的潜力。