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目的分离鉴定海洋链霉菌Streptomyces sp.7-145产生的抗耐药菌活性成分。方法通过活性追踪,利用大孔吸附树脂、凝胶、正反相色谱等多种色谱技术分离纯化活性成分;通过紫外光谱、质谱、核磁共振谱等波谱学方法鉴定其结构。利用琼脂稀释法和微量肉汤稀释法分别测定所得化合物的抗耐药菌和抗结核活性,利用MTT法评价其细胞毒性。结果从中分离鉴定了4个活性化合物,其结构分别确定为洋橄榄叶素(1)、11-O-甲基洋橄榄叶素(2)、11,11’-O-二甲基洋橄榄叶素(3)、14’-去乙基-14’-甲基洋橄榄叶素(4)。化合物1~4对甲氧西林耐药的金黄色葡萄球菌(MRSA)和万古霉素耐药的肠球菌(VRE)等革兰阳性耐药菌具有较强的抗菌活性,最低抑菌浓度(MIC)为1~16μg/mL;所有化合物对结核分枝杆菌H37Rv株显示出显著的抑制活性(MIC:0.5~4μg/mL),其中化合物1对结核分枝杆菌多重耐药(MDR)、广泛耐药(XDR)等耐药株也表现出较强的抑制活性(MIC:0.5~1μg/mL);1和2对人肝细胞(L02)、肾上皮细胞(293T)和乳腺癌细胞(MCF-7)具有较强的细胞毒活性,IC50值为0.14~0.28μmol/L。结论化合物1~4具有较强的体外抗MRSA、VRE等耐药菌活性。首次发现洋橄榄叶素(1)具有体外抗结核分枝杆菌标准株、多重耐药以及广泛耐药株活性。化合物1和2对人正常肝、肾上皮细胞具有细胞毒性。
OBJECTIVE To isolate and identify the anti-drug resistant active ingredients produced by Streptomyces sp.7-145. Methods The active constituents were isolated and purified by macroporous adsorption resin, gel and reversed-phase chromatography. Their structures were identified by UV spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. The anti-drug-resistant and anti-TB activity of the obtained compounds were respectively determined by agar dilution method and micro broth dilution method, and their cytotoxicity was evaluated by MTT method. Results Four active compounds were isolated and identified. Their structures were identified as Euclid (1), 11-O-methyl olivellin (2), 11,11’-O-dimethyl olive leaves (3), 14’-deethyl-14’-methylephedrine (4). Compounds 1 to 4 have strong antibacterial activity against gram-positive resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The MICs ) Was 1 ~ 16μg / mL; all compounds showed significant inhibitory activity against Mycobacterium tuberculosis H37Rv strain (MIC: 0.5-4μg / mL), of which compound 1 was multi-drug resistant to M. tuberculosis (MDR) (MIC: 0.5 ~ 1μg / mL); 1 and 2 had inhibitory effects on the resistance of human hepatocytes (L02), renal epithelial cells (293T) and breast cancer cells 7) has a strong cytotoxic activity, IC50 value of 0.14 ~ 0.28μmol / L. Conclusion Compounds 1 ~ 4 have strong resistance to MRSA, VRE and other antibacterial activity in vitro. The first discovery of foreign olive hormone (1) with in vitro anti-TB Mycobacterium tuberculosis standard strains, multi-drug resistance and extensive drug-resistant strains activity. Compounds 1 and 2 are cytotoxic to human normal liver and kidney epithelial cells.