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 s...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(IC_(50))of approximately 1μmol·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.展开更多
A chemical investigation on the fermentation products of Sanghuangporus sanghuang led to the isolation and identification of fourteen secondary metabolites(1-14)including eight sesquiterpenoids(1-8)and six polyphenols...A chemical investigation on the fermentation products of Sanghuangporus sanghuang led to the isolation and identification of fourteen secondary metabolites(1-14)including eight sesquiterpenoids(1-8)and six polyphenols(9-14).Compounds1-3 were sesquiterpenes with new structures which were elucidated based on NMR spectroscopy,high resolution mass spectrometry(HRMS)and electronic circular dichroism(ECD)data.All the isolates were tested for their stimulation effects on glucose uptake in insulin-resistant HepG2 cells,and cellular antioxidant activity.Compounds 9-12 were subjected to molecular docking experiment to primarily evaluate their anti-coronavirus(SARS-CoV-2)activity.As a result,compounds 9-12 were found to increase the glucose uptake of insulin-resistant HepG2 cells by 18.1%,62.7%,33.7%and 21.4%at the dose of 50μmol·L^(-1),respectively.Compounds 9-12 also showed good cellular antioxidant activities with CAA_(50)values of 12.23,23.11,5.31 and 16.04μmol·L^(-1),respectively.Molecular docking between COVID-19 M^(pro)and compounds 9-12 indicated potential SARS-CoV-2 inhibitory activity of these four compounds.This work provides new insights for the potential role of the medicinal mushroom S.sanghuang as drugs and functional foods.展开更多
基金supported by the National Natural Science Foundation of China(81630089,81703398,81872780,and 81803410)the Beijing Natural Science Foundation,China(7214286)+1 种基金the Drug Innovation Major Project of China(2018ZX09711001-006-011,2018ZX09735001-002,and 2018ZX09711001-007)the CAMS Innovation Fund for Medical Sciences(2018-I2M-3-005 and 2020-I2M-2-010)。
文摘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(IC_(50))of approximately 1μmol·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.
基金supported by the National Key R&D Program of China(No.2018YFD0400203)the National Natural Science Foundation of China(No.81673334)。
文摘A chemical investigation on the fermentation products of Sanghuangporus sanghuang led to the isolation and identification of fourteen secondary metabolites(1-14)including eight sesquiterpenoids(1-8)and six polyphenols(9-14).Compounds1-3 were sesquiterpenes with new structures which were elucidated based on NMR spectroscopy,high resolution mass spectrometry(HRMS)and electronic circular dichroism(ECD)data.All the isolates were tested for their stimulation effects on glucose uptake in insulin-resistant HepG2 cells,and cellular antioxidant activity.Compounds 9-12 were subjected to molecular docking experiment to primarily evaluate their anti-coronavirus(SARS-CoV-2)activity.As a result,compounds 9-12 were found to increase the glucose uptake of insulin-resistant HepG2 cells by 18.1%,62.7%,33.7%and 21.4%at the dose of 50μmol·L^(-1),respectively.Compounds 9-12 also showed good cellular antioxidant activities with CAA_(50)values of 12.23,23.11,5.31 and 16.04μmol·L^(-1),respectively.Molecular docking between COVID-19 M^(pro)and compounds 9-12 indicated potential SARS-CoV-2 inhibitory activity of these four compounds.This work provides new insights for the potential role of the medicinal mushroom S.sanghuang as drugs and functional foods.
