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多组学导向的链霉菌1647产生的奥米克欣的发现——一组抗甲型流感病毒和冠状病毒HCoV-229E的活性类四肽化合物
Hongmin Sun, Xingxing Li, Minghua Chen, Ming Zhong, Yihua Li, Kun Wang, Yu Du, Xin Zhen, Rongmei Gao, Yexiang Wu, Yuanyuan Shi, Liyan Yu, Yongsheng Che, Yuhuan Li, Jian-Dong Jiang, Bin Hong, Shuyi Si
工程（英文） ›› 2022, Vol. 16 ›› Issue (9) : 176-186.
PDF(3697 KB)
PDF(3697 KB)
多组学导向的链霉菌1647产生的奥米克欣的发现——一组抗甲型流感病毒和冠状病毒HCoV-229E的活性类四肽化合物
Multi-Omics-Guided Discovery of Omicsynins Produced by Streptomyces sp. 1647: Pseudo-Tetrapeptides Active Against Influenza A Viruses and Coronavirus HCoV-229E
微生物具有产生抗病毒抗生素以保护细胞存活的机制。链霉菌（Streptomyces sp.）1647 是20 世纪70 年代从中国南方土壤中分离的一株链霉菌，其发酵液显示优良的抗甲型流感病毒（IAV）活性，但其抗病毒活性成分始终没有得到有效的分离和结构鉴定。本研究综合利用多组学研究策略，从这株链霉菌中成功分离得到抗病毒活性成分。利用抗生素及次级代谢产物分析软件（antiSMASH）分析该菌株的基因组序列信息，发现其中可能含有38 个次级代谢产物生物合成基因簇（BGC）。经过生物活性导向的比较转录组学分析，初步锁定三个可能的目标抗病毒活性化合物的生物合成基因簇。通过生物信息学分析及对基因簇36 中调节基因和生物合成基因的遗传操作，确定了基因簇36 为抗病毒活性化合物的生物合成基因簇。对野生株和不同重组菌株发酵产物进行基于生物活性导向的质谱数据分子网络分析，初步确定了抗病毒成分是一组化学结构类似物。最后通过高分辨质谱和二维核磁共振波谱分析，确定了抗病毒活性成分为包括18 个含有脲基的类四肽结构，取名奥米克欣（omicsynin）A1~A6、奥米克欣B1~B6 和奥米克欣C1~C6，其中11 个（奥米克欣A1、奥米克欣A2、奥米克欣A6、奥米克欣B1~B3、奥米克欣B5、奥米克欣B6、奥米克欣C1、奥米克欣C2 和奥米克欣C6）是新结构化合物。奥米克欣B1~B4 显示出优良的抗甲型流感病毒活性，其50%抑制浓度（IC50）在1 μmol·L−1左右，选择指数（SI）为100~300。奥米克欣B1~B4 同时显示出对人冠状病毒HCoV-229E的显著抑制活性。综上，通过综合利用多组学技术与数据分析，从链霉菌1647 发酵产物中发现了一组新型的具有抗病毒活性的类四肽化合物，说明微生物次级代谢产物是新型抗病毒抗生素的宝贵资源。
Many microorganisms have mechanisms that protect cells against attack from viruses. The fermentation components of Streptomyces sp. 1647 exhibit potent anti-influenza A virus (IAV) activity. This strain was isolated from soil in southern China in the 1970s, but the chemical nature of its antiviral substance(s) has remained unknown until now. We used an integrated multi-omics strategy to identify the antiviral agents from this streptomycete. The antibiotics and Secondary Metabolite Analysis Shell (antiSMASH) analysis of its genome sequence revealed 38 biosynthetic gene clusters (BGCs) for secondary metabolites, and the target BGCs possibly responsible for the production of antiviral components were narrowed down to three BGCs by bioactivity-guided comparative transcriptomics analysis. Through bioinformatics analysis and genetic manipulation of the regulators and a biosynthetic gene, cluster 36 was identified as the BGC responsible for the biosynthesis of the antiviral compounds. Bioactivity-based molecular networking analysis of mass spectrometric data from different recombinant strains illustrated that the antiviral compounds were a class of structural analogues. Finally, 18 pseudo-tetrapeptides with an internal ureido linkage, omicsynins A1–A6, B1–B6, and C1–C6, were identified and/or isolated from fermentation broth. Among them, 11 compounds (omicsynins A1, A2, A6, B1–B3, B5, B6, C1, C2, and C6) are new compounds. Omicsynins B1–B4 exhibited potent antiviral activity against IAV with the 50% inhibitory concentration (IC50) of approximately 1 µmol∙L–1 and a selectivity index (SI) ranging from 100 to 300. Omicsynins B1–B4 also showed significant antiviral activity against human coronavirus HCoV-229E. By integrating multi-omics data, we discovered a number of novel antiviral pseudo-tetrapeptides produced by Streptomyces sp. 1647, indicating that the secondary metabolites of microorganisms are a valuable source of novel antivirals.
多组学 / 抗甲型流感病毒 / 抗冠状病毒 / 链霉菌1647 / 类四肽化合物
Multi-omics / Anti-influenza A virus / Anti-coronavirus / Streptomyces sp. 1647 / Pseudo-tetrapeptides
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