Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production.
Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production.
复制标题
深海来源的索马里链霉菌 SCSIO ZH66 的 wbl 基因突变菌株中抗霉素型缩酚肽的发现及其对促炎细胞因子产生的影响
DOI：
10.3389/fmicb.2017.00678
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发表时间：
2017
影响因子：
5.2
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Li H;Huang H;Hou L;Ju J;Li W
深海微生物是新型生物活性化合物的丰富来源，与陆地微生物相比，深海微生物具有独特的遗传系统和生物合成途径，能够在极端的生存环境中生存。然而，在正常的实验室条件下，许多深海微生物次级代谢途径仍然“神秘”。调控全局调控因子是引发隐性次级代谢产物产生的有效途径之一。在本研究中，通过各种色谱纯化方法的组合，我们从深海来源的索马里链霉菌SCSIO ZH 66的ΔwblAso突变株中获得了一种新的抗霉素型缩酚酸肽，其具有3-氨基水杨酸酯取代保守的3-甲酰氨基水杨酸酯部分，沿着两种已知的类似物（2和3）。1-3的结构基于广泛的光谱分析（包括LC-MS和NMR）来阐明。在有效的抗炎活性评价中，化合物2显示出对卵清蛋白刺激的脾细胞中IL-5产生的强抑制活性，IC 50值为0.57 μM，而化合物1和3显示出温和的作用（>10 μM），这可能归因于它们的不同侧链取代。此外，化合物1-3对人脐静脉内皮细胞显示出非常弱的细胞毒性，LD 50值分别为62.6、34.6和192.9 μM，这远远超过了它们的IL-5抑制活性。这些结果表明，这些化合物具有良好的潜力，进一步用于抗炎药物的开发。
Deepsea microbes are a rich source of novel bioactive compounds, which have developed unique genetic systems as well as biosynthetic pathways compared with those of terrestrial microbes in order to survive in extreme living environment. However, a large variety of deepsea-microbial secondary metabolic pathways remain “cryptic” under the normal laboratory conditions. Manipulation of global regulators is one of the effective approaches for triggering the production of cryptic secondary metabolites. In this study, by combination of various chromatographic purification process, we obtained somalimycin (1), a new antimycin-type depsipeptide, with an unusual substitution of 3-aminosalicylate instead of conserved 3-formamidosalicylate moiety, along with two known (2 and 3) analogs from the ΔwblAso mutant strain of deepsea-derived Streptomyces somaliensis SCSIO ZH66. The structures of 1–3 were elucidated on the basis of extensive spectroscopic analyses including LC-MS and NMR. In the evaluation of potent anti-inflammatory activity, compound 2 exhibited strong inhibitory activity on the IL-5 production in ovalbumin-stimulated splenocytes with IC50 value of 0.57 μM, while 1 and 3 displayed mild effect (>10 μM), which might be attributed to their different side-chain substitutions. Moreover, compounds 1–3 showed very weak cytotoxicity against human umbilical vein endothelial cells with LD50 values of 62.6, 34.6, and 192.9 μM, respectively, which were far over their IL-5 inhibitory activity. These results indicated that these compounds have good potential for further use in anti-inflammatory drug development.