海洋链霉菌IMB3-202产生的吲哚咔唑生物碱  

Identification of indolocarbazoles from the marine-derived Streptomyces sp.IMB3-202

作　　者：王冕 郝晓萌 李娇 胡媛媛 关艳[1] 王以光[1] 甘茂罗[1] 肖春玲[1] WANG Mian;HAO Xiao-meng;LI Jiao;HU Yuan-yuan;GUAN Yan;WANG Yi-guang;GAN Mao-luo;XIAO Chun-ling(National Laboratory for Screening New Microbial Drugs,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

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国家新药微生物筛选实验室,北京100050

出　　处：《中国医药生物技术》2018年第2期137-144,共8页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81273414);中央高校基本科研业务费专项资金(3332016062);国家"重大新药创制"科技重大专项(2018ZX09711001-007-002);中国医学科学院医学与健康创新工程(2016-I2M-2-002)

摘　　要：目的分离鉴定海洋链霉菌IMB3-202产生的抗菌和抗肿瘤活性产物。方法利用Anti SMASH对菌株基因组进行生物信息学分析;运用多种色谱手段分离纯化IMB3-202的活性产物;通过波谱学方法鉴定化合物的化学结构;采用微量肉汤稀释法和MTT法分别测定化合物的抗菌和细胞毒活性。结果菌株IMB3-202基因组含有一条吲哚咔唑类生物合成基因簇。通过发酵条件优化,从中分离鉴定了4个吲哚咔唑类化合物,结构分别确定为星形孢菌素、3'-O-去甲基星形孢菌素、holyrine A和K252c。星形孢菌素、3'-O-去甲基星形孢菌素和holyrine A对HeLa细胞、HCT116和MCF-7等肿瘤细胞具有很强的抑制活性,IC_(50)值为0.75~1192.8 nmol/L。星形孢菌素对金黄色葡萄球菌和白色念珠菌显示出较弱的抗菌活性,最低抑菌浓度值为128μg/ml。结论通过基因组序列分析,可以在基因水平上预测产物结构,快速识别特定类型产物。Objective To identify the antibacterial and cytotoxic products from the marine-derived Streptomyces sp.IMB3-202.Methods The potential biosynthetic gene clusters were analyzed using antiSMASH 3.0.The metabolites from Streptomyces sp.IMB3-202 were isolated and purified by a combination of various chromotographic techniques.The structures were elucidated by spectroscopic analysis.The antibacterial and cytotoxic activities of the products were evaluated by using broth micro-dilution and MTT methods,respectively.Results The bioinformatic analysis revealed that the geome of strain IMB3-202 contained a gene cluster highly homologous to the known indolocarbazole biosynthetic gene cluster.Four indolocarbazole analogues were obtained.Their structures were identified as staurosporine(1),3'-O-demethylstaurosporine(2),holyrine A(3)and K252c(4).Compounds 1-3 displayed potent cytotoxicity against human HeLa,HCT116,and MCF-7 cancer cell lines with IC50 values ranging from 0.75 to 1192.8 nmol/L.Compound 1 showed weak antibacterial activity against Staphylococcus aureus and Candida albicans(MIC:128μg/ml).Conclusion Four indolocarbazole analogues were obtained from the marine-derived Streptomyces sp.IMB3-202 by genomic analysis.

关 键 词：海洋放线菌 吲哚咔唑 星形孢菌素 基因组分析 细胞毒活性 

分 类 号：R915[医药卫生—微生物与生化药学]