分子网络辅助发现和组合生物合成新型抗菌截短侧耳素。
Molecular networking assisted discovery and combinatorial biosynthesis of new antimicrobial pleuromutilins.
机构信息
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
Key Laboratory of Structure-Based Drug Design & Discovery of Education, College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
出版信息
Eur J Med Chem. 2022 Dec 5;243:114713. doi: 10.1016/j.ejmech.2022.114713. Epub 2022 Sep 1.
Pleuromutilins, the unique fungal metabolites possessing 5/6/8 tricyclic skeleton, are potent antibacterial leading compounds for the development of new antibiotics. We applied the MS/MS molecular networking technique and the combinatorial biosynthesis approach to discover new pleuromutilin analogues. Ten pleuromutilin derivatives including seven new compounds (1-7) were obtained from the solid culture of Omphalina mutila. The gene cluster for the biosynthesis of pleuromutilins in the mushroom of O. mutila was identified and further expressed in yeast. Nine pleuromutilin-type diterpenes including three new "unnatural" pleuromutilins (16-18) were generated in a GGPP-engineered Saccharomyces cerevisiae. The antimicrobial bioassays indicated that compounds 3, 9, 10, 15, and 17 exhibited potent inhibition against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). Several pleuromutilins were found to show immunomodulatory activities by promoting the cell viability, enhancing the ROS and NO production, or increasing the levels of proinflammatory cytokines IL-6 and TNF-α in the macrophage RAW 264.7. The structure-activity relationship for pleuromutilins was analyzed.
苦马豆素是具有 5/6/8 个三环骨架的独特真菌代谢产物，是开发新型抗生素的强效抗菌先导化合物。我们应用 MS/MS 分子网络技术和组合生物合成方法来发现新的苦马豆素类似物。从 Omphalina mutila 的固体培养物中获得了包括七个新化合物（1-7）在内的十种苦马豆素衍生物。鉴定了蘑菇 O. mutila 中苦马豆素生物合成的基因簇，并在酵母中进一步表达。在 GGPP 工程化酿酒酵母中产生了包括三种新的“非天然”苦马豆素（16-18）在内的九种苦马豆素型二萜。抗菌生物测定表明，化合物 3、9、10、15 和 17 对耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素粪肠球菌（VRE）具有很强的抑制作用。一些苦马豆素被发现具有免疫调节活性，通过促进细胞活力、增强 ROS 和 NO 的产生、或增加巨噬细胞 RAW 264.7 中的促炎细胞因子 IL-6 和 TNF-α 的水平。分析了苦马豆素的构效关系。
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