药学学报, 2019, 54(11): 2031-2038
引用本文:
崔阿龙, 胡辛欣, 高岩, 金洁, 易红, 陈阳, 何琪杨, 游雪甫, 李卓荣. 新型多黏菌素B衍生物的设计合成及生物功能研究[J]. 药学学报, 2019, 54(11): 2031-2038.
CUI A-long, HU Xin-xin, GAO Yan, JIN Jie, YI Hong, CHEN Yang, HE Qi-yang, YOU Xue-fu, LI Zhuo-rong. Design, synthesis, and biological evaluation of novel polymyxin B analogues[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 2031-2038.

新型多黏菌素B衍生物的设计合成及生物功能研究
崔阿龙, 胡辛欣, 高岩, 金洁, 易红, 陈阳, 何琪杨, 游雪甫, 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:
多黏菌素B和多黏菌素E(黏菌素)成为治疗多药耐药革兰氏阴性菌的“最后一道防线”,但是多黏菌素存在严重的肾毒性,限制了其临床使用。因此,急需研发新型高效、低毒的多黏菌素衍生物。本研究通过改变N-取代脂肪酰基链或6位D-Phe的疏水性和体积设计合成两类多黏菌素B衍生物20个,并评价其生物活性。衍生物结构经高分辨质谱(HR-MS)和核磁共振氢谱(1H NMR)确证,与多黏菌素B(MIC:0.5~2 μg·mL-1,CC50:120.3±6.0 μg·mL-1)相比,衍生物7e(MIC:0.5~4 μg·mL-1)和7l(MIC:0.25~2 μg·mL-1)对测定的耐药或敏感的大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌和铜绿假单胞菌显示出相当或提高的抗菌活性,同时衍生物7l(CC50:217.1±13.2 μg·mL-1)的肾细胞毒性降低。本研究为多黏菌素B的构效关系研究奠定基础。
关键词:    革兰氏阴性菌      多黏菌素B      新衍生物      抗菌活性      肾毒性     
Design, synthesis, and biological evaluation of novel polymyxin B analogues
CUI A-long, HU Xin-xin, GAO Yan, JIN Jie, YI Hong, CHEN Yang, HE Qi-yang, YOU Xue-fu, LI Zhuo-rong
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Polymyxin B and polymyxin E (colistin) are increasingly used as last-resort drugs for treatment of infections caused by multidrug-resistant gram-negative pathogens. Unfortunately, the application was limited due to the serious side effects, especially nephrotoxicity. Very recently, the need for developing more tolerated and more effective polymyxin analogues has grown. This study details the design, synthesis, and evaluation of two classes of polymyxin B analogues with varying hydrophobicity and bulkiness at the N-terminal fatty acyl chain or position 6 amino acid. 20 polymyxin B analogues were synthesized and the chemical structures of the analogues were confirmed by HR-MS and 1H NMR spectra. Compounds 7e (MIC:0.5-4 μg·mL-1) and 7l (MIC:0.25-2 μg·mL-1) showed similar or better antimicrobial activity against both susceptible and resistant strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to polymyxin B (MIC:0.5-2 μg·mL-1). Besides, compound 7l (CC50:217.1±13.2 μg·mL-1) displayed noticeably decreased renal cytotoxicity compared to polymyxin B (CC50:120.3±6.0 μg·mL-1). This work establishes the base of further study on the structure-activity relationship of polymyxin B.
Key words:    gram-negative pathogens    polymyxin B    novel analogues    antimicrobial activity    nephrotoxicity   
收稿日期: 2019-06-21
DOI: 10.16438/j.0513-4870.2019-0500
基金项目: 国家自然科学基金面上项目(81773585);中国医学科学院医学与健康科技创新工程(2017-I2M-1-012).
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参考文献:
[1] Velkov T, Thompson PE, Nation RL, et al. Structure-activity relationships of polymyxin antibiotic[J]. J Med Chem, 2010, 53: 1898-1916.
[2] Benedict RG, Langlykke AF. Antibiotic activity of Bacillus polymyxa[J]. J Bacteriol, 1947, 54: 24-25.
[3] Shoji J, Hinoo H, Wakisaka Y, et al. Isolation of two new polymyxin group antibiotics. (Studies on antibiotics from the genus Bacillus. XX)[J]. J Antibiot, 1977, 30: 1029-1034.
[4] Terabe S, Konaka R, Shoji J. Separation of polymyxins and octapeptins by high-performance liquid chromatography[J]. J Chromatogr A, 1979, 173: 313-320.
[5] Brown JM, Dorman DC, Roy LP. Acute renal failure due to overdosage of colistin[J]. Med J Aust, 1970, 2: 923-924.
[6] Price DJ, Graham DI. Effects of large doses of colistin sulphomethate sodium on renal function[J]. Br Med J, 1970, 4: 525-527.
[7] Koch-Weser J, Sidel VW, Federman EB, et al. Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy[J]. Ann Intern Med, 1970, 72: 857-868.
[8] Kubin CJ, Ellman TM, Phadke V, et al. Incidence and predictors of acute kidney injury associated with intravenous polymyxin B therapy[J]. J Infect, 2012, 65: 80-87.
[9] Akajagbor DS, Wilson SL, Shere-Wolfe KD, et al. Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin B in critically ill patients at a tertiary care medical center[J]. Clin Infect Dis, 2013, 57: 1300-1303.
[10] Quale J, Shah N, Kelly P, et al. Activity of polymyxin B and the novel polymyxin analogue CB-182,804 against contemporary Gram-negative pathogens in New York City[J]. Microb Drug Resist, 2012, 18: 132-136.
[11] Magee TV, Brown MF, Starr JT, et al. Discovery of Dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections[J]. J Med Chem, 2013, 56: 5079-5093.
[12] Brown P, Dawson MJ. Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections[J]. J Antibiot, 2017, 70: 386-394.
[13] Gallardo-Godoy A, Muldoon C, Becker B, et al. Activity and predicted nephrotoxicity of synthetic antibiotics based on polymyxin B[J]. J Med Chem, 2016, 59: 1068-1077.
[14] Velkov T, Roberts KD, Nation RL, et al. Teaching ‘old’ polymyxins new tricks: new-generation lipopeptides targeting gram-negative ‘superbugs’[J]. ACS Chem Biol, 2014, 9: 1172-1177.
[15] Cui AL, Hu XX, Gao Y, et al. Synthesis and bioactivity investigation of the individual components of cyclic lipopeptide antibiotics[J]. J Med Chem, 2018, 61: 1845-1857.
[16] Geske GD, Wezeman RJ, Siegel AP, et al. Small molecule inhibitors of bacterial quorum sensing and biofilm formation[J]. J Am Chem Soc, 2005, 127: 12762-12763.