药学学报, 2021, 56(5): 1424-1428
引用本文:
崔阿龙, 杨鹤显, 薛司徒, 孙连奇, 金洁, 易红, 李卓荣*. 新型阳离子蜂毒肽结构优化及衍生物的抗菌活性研究[J]. 药学学报, 2021, 56(5): 1424-1428.
CUI A-long, YANG He-xian, XUE Si-tu, SUN Lian-qi, JIN Jie, YI Hong, LI Zhuo-rong*. Structure modification and antimicrobial activity of novel cationic melittin analogues[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1424-1428.

新型阳离子蜂毒肽结构优化及衍生物的抗菌活性研究
崔阿龙, 杨鹤显, 薛司徒, 孙连奇, 金洁, 易红, 李卓荣*
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
摘要:
蜂毒肽对耐药菌具有较强的抗菌活性,但是蜂毒肽存在严重的溶血作用,限制了其临床使用。因此,需要研发新型高抗菌活性、低溶血作用的蜂毒肽衍生物。本研究通过改变蜂毒肽的氨基酸疏水性、极性和正电荷数量设计合成新衍生物20个,并评价其抗菌活性和溶血作用。结果表明,8个衍生物对阳性菌的抗菌活性保持或提高(MIC:1~4 μg·mL-1),16个衍生物的溶血作用(HC50≥ 11.9 μg·mL-1)降低。与蜂毒肽(MIC:4μg·mL-1,HC50:5.3±0.4 μg·mL-1)相比,衍生物13(MIC:2~4 μg·mL-1)和15(MIC:1~2 μg·mL-1)对测定的耐药或敏感的金葡菌和屎肠球菌显示出相当或提高的抗菌活性,并且衍生物13的溶血作用(HC50:24.0±4.3 μg·mL-1)明显降低。本研究为蜂毒肽的构效关系与构毒关系研究奠定基础。
关键词:    革兰阳性菌      蜂毒肽      新衍生物      抗菌活性      溶血作用     
Structure modification and antimicrobial activity of novel cationic melittin analogues
CUI A-long, YANG He-xian, XUE Si-tu, SUN Lian-qi, JIN Jie, YI Hong, LI Zhuo-rong*
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Melittin exhibits high antibacterial potency against drug-resistant bacteria. However, the clinical utility of melittin is limited by its serious hemolytic activity. Thus, the need for developing novel melittin analogues with high antimicrobial activity and low hemolytic activity has grown. We designed, synthesized, and evaluated 20 novel melittin analogues with varying hydrophobic, polar or positively charged amino acids. The results showed that 8 compounds had antimicrobial activity (MIC:1-4 μg·mL-1) against gram-positive pathogens equal to or better than that of melittin, and 16 compounds had low hemolytic activity (HC50 ≥ 11.9 μg·mL-1). Compounds 13 (MIC:2-4 μg·mL-1) and 15 (MIC:1-2 μg·mL-1) showed equal or better antimicrobial activity against both susceptible and resistant strains of Staphylococcus aureus and Enterococcus faecium compared to melittin (MIC:4 μg·mL-1). Compound 13 (HC50:24.0±4.3 μg·mL-1) displayed noticeably decreased hemolytic activity compared to melittin (HC50:5.3±0.4 μg·mL-1). This work established a base for further study on the structure-activity relationships and structure-toxicity relationships of melittin.
Key words:    gram-positive pathogen    melittin    novel analogue    antimicrobial activity    hemolytic activity   
收稿日期: 2021-02-05
DOI: 10.16438/j.0513-4870.2021-0190
基金项目: 国家自然科学基金资助项目(82003600);中国医学科学院医学与健康科技创新工程(2017-I2M-1-012);重大新药创制科技重大专项(2019ZX09721001-004-006).
通讯作者: 李卓荣,Tel:86-10-63027185,E-mail:l-z-r@263.net
Email: l-z-r@263.net
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