链霉菌Streptomyces sp.CPCC 203679的次级代谢产物研究  

Study on secondary metabolites from Streptomyces sp.CPCC 203679

作　　者：郭哲 刘梦[2,3] 赵建元 胡辛欣[1] 徐建[1,4] 柏菁璘[1] 岑山[1] 游雪甫 余利岩[1] 张德武[1] Guo Zhe;Liu Meng;Zhao Jianyuan;Hu Xinxin;Xu Jian;Bai Jinglin;Cen Shan;You Xuefu;Yu Liyan;Zhang Dewu(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050;College of Applied Arts and Science,Beijing Union University,Beijing 100023;Beijing Children’s Hospital,Capital Medical University,Beijing 100045;Beijing Key Laboratory of Drug Resistance Tuberculosis Research,Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing Chest Hospital,Capital Medical University,Beijing 101149)

机构地区：[1]中国医学科学院&北京协和医学院医药生物技术研究所,北京100050 [2]北京联合大学应用文理学院,北京100023 [3]首都医科大学附属北京儿童医院,北京100045 [4]首都医科大学附属北京胸科医院耐药结核病研究北京市重点实验室/北京市结核病胸部肿瘤研究所药物研究室,北京101149

出　　处：《中国抗生素杂志》2025年第2期185-193,共9页Chinese Journal of Antibiotics

基　　金：国家自然科学基金项目(No.82073744和81402835);中国医学科学院医学与健康科技创新工程(No.2021-1-I2M-055);国家微生物资源平台项目(No.NMRC-2023-3)。

摘　　要：目的研究链霉菌Streptomyces sp.CPCC 203679的活性次级代谢产物,分析其次级代谢产物生物合成基因簇,并挖掘其产生次级代谢产物的潜力。方法通过正相硅胶柱色谱、Sephadex LH-20凝胶柱色谱和半制备HPLC等方法进行分离纯化。利用质谱、核磁共振波谱等技术进行化合物的结构鉴定。利用Illumina HiSeq测序技术对菌株CPCC 203679进行基因组测序,采用antiSMASH(v7.1.0)在线工具分析其次级代谢产物生物合成基因簇。对大环内酯类化合物进行抗病毒和抗菌活性测试。结果从链霉菌CPCC 203679发酵液中分离鉴定了4个化合物,分别为:勃利霉素A(1)、勃利霉素F(2)、5'-脱氧-5'-甲硫肌苷(3)、环(L-丙氨酸-L-异亮氨酸)二肽(4)。化合物1和2显示良好的抗甲型流感病毒活性,IC50值分别为2.4和4.7μmol/L,化合物1还显示一定的抗革兰阳性菌和抗结核分枝杆菌活性。全基因组测序显示,菌株CPCC 203679的基因组序列全长8,055,535 bp,平均(G+C)含量为72.58%,共编码7507个基因,预测到44个生物合成基因簇。结论从链霉菌Streptomyces sp.CPCC 203679中分离得到2个活性良好的大环内酯类化合物,并首次报道了勃利霉素类大环内酯的抗甲型流感病毒、抗艾滋病病毒和抗结核分枝杆菌的活性。该菌株具有丰富的次级代谢产物生物合成基因簇,具有进一步挖掘新的次级代谢产物的价值。Objective To investigate bioactive secondary metabolites from Streptomyces sp.CPCC 203679,analyzed the biosynthesis gene cluster of secondary metabolites,and explored its potential to produce secondary metabolites.Methods The secondary metabolites were isolated and purified by silica gel column chromatography,Sephadex LH-20 column chromatography and semi-preparative HPLC.Their structures were elucidated by extensive spectroscopic analyses,such as mass spectrum and NMR.Streptomyces sp.CPCC 203679 was sequenced by Illumina HiSeq sequencing technology to mine secondary metabolite biosynthesis gene clusters using antiSMASH(v7.1.0)online tool.The isolated macrolides were evaluated for their antiviral and antibacterial activities.Results Four compounds were isolated from the fermentation broth of Streptomyces sp.CPCC 203679 and elucidated as borrelidin A(1),borrelidin F(2),5'-deoxy-5'-methylthioinosine(3),and cyclo-(L-Ala-L-Ile)(4).Compounds 1 and 2 showed significant anti-influenza A virus(IAV)activities,with IC50 values of 2.4 and 4.7μmol/L,respectively.Compound 1 also displayed broad-spectrum activities against Gram-positive bacteria and Mycobaeterium tuberculosis.Whole-genome sequencing revealed that the size of the genome was 8,055,535 bp with an average G+C content of 72.58%,which encoded 7507 genes,and a total of 44 biosynthetic gene clusters were predicted.Conclusion Two bioactive macrolides were obtained from the fermentation broth of Streptomyces sp.CPCC 203679.The anti-IAV,anti-HIV,and anti-Mycobacterium tuberculosis activities of borrelidin derivatives were reported for the first time.This strain has abundant secondary metabolite biosynthesis gene clusters,which has the value of further exploring new secondary metabolites.

关 键 词：链霉菌 次级代谢产物 抗病毒活性 抗菌活性 全基因组测序 

分 类 号：R978[医药卫生—药品]