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 iso-lated 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 tar-get 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 respon-sible 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.

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

NHC Key Laboratory of Biotechnology of Antibiotics,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;CAMS Key Laboratory of Synthetic Biology for Drug Innovation,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;CAMS Key Laboratory of Antiviral Drug Research,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China

工程（英文）

[1]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-.Multi-Omics-Guided Discovery of Omicsynins Produced by Streptomyces sp.1647:Pseudo-Tetrapeptides Active Against Influenza A Viruses and Coronavirus HCoV-229E)[J].工程（英文）,2022(09):176-186

Omicsynins,Tetrapeptides,streptomycete,Bioactivity,tetrapeptides,ureido,omicsynins

Multi,Guided,Discovery,Produced,by,Streptomyces,Pseudo,Active,Against,Influenza,Viruses,Coronavirus,HCoV,229E,Many,microorganisms,have,mechanisms,that,protect,cells,against,attack,from,viruses,fermentation,components,potent,influenza,IAV,This,was,soil,southern,China,1970s,but,chemical,nature,its,substance,has,remained,unknown,until,We,used,integrated,multi,strategy,identify,agents,this,antibiotics,Secondary,Metabolite,Analysis,Shell,antiSMASH,analysis,genome,sequence,revealed,biosynthetic,clusters,BGCs,secondary,metabolites,tar,get,possibly,responsible,production,were,narrowed,down,three,bioactivity,guided,comparative,transcriptomics,Through,bioinformatics,genetic,manipulation,regulators,identified,biosynthesis,compounds,molecular,networking,mass,spectrometric,data,different,recombinant,strains,illustrated,class,structural,analogues,Finally,pseudo,internal,linkage,A1,A6,B1,B6,C1,C6,isolated,broth,Among,them,A2,B3,B5,C2,are,new,B4,exhibited,inhibitory,concentration,IC50,approximately,selectivity,SI,ranging,also,showed,significant,human,coronavirus,By,integrating,discovered,number,novel,produced,indicating,valuable,source,antivirals

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