靶向铜绿假单胞菌(Pseudomonas aeruginosa)粘肽合成酶PBP3的抗菌先导化合物的虚拟筛选及活性研究
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浙江省自然科学基金(LY12C19011);食品科学与工程浙江省重中之重一级学科资助项目(JYTSP20141052)


Virtual screening and antibacterial activity of lead compounds targeting to penicillin-binding protein 3 (PBP3) of Pseudomonas aeruginosa
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    摘要:

    [目的] 开发出与铜绿假单胞菌粘肽合成酶PBP3有高亲和力,具有全新结构的先导化合物。[方法] 以铜绿假单胞菌粘肽合成酶PBP3为靶点,通过分子对接软件DOCK6.5,对含有104万个小分子化合物的数据库进行了大规模虚拟筛选,选取结构相对简单的中选化合物进行合成,得到先导化合物,并验证其抑菌活性。[结果] 通过grid score进行第一轮初筛,筛选出grid score分值小于-30 kcal/mol的6万个化合物,接着以amber score进行第二轮筛选,筛出amber score分值小于-20 kcal/mol的化合物约200个。最终,经过观察分析,从中挑选出4种打分高并且结构新颖的小分子化合物作为先导化合物。合成出的先导化合物及其衍生物对铜绿假单胞菌等常见微生物的最小抑菌浓度(MIC)在175-275 μg/mL之间,对革兰氏阴性菌和阳性菌均有效,MIC值比作为阳性对照的磺胺嘧啶更低,说明先导化合物具有较好的抗菌活性。[结论] 这些先导化合物可以进一步开发为新型抗菌药物,用于解决铜绿假单胞菌的耐药性问题。

    Abstract:

    [Objective] This study was carried out to obtain lead compounds targeting penicillin-binding protein 3 (PBP3) of Pseudomonas aeruginosa by virtual screening. [Methods] UCSF dock 6.5 was used for the virtual screening from a database containing 1.04 million small molecules. Hit compounds with simple structures were synthesized and then evaluated for their antibacterial activities. [Results] Grid score was used for the first round of screening, and 60000 small molecules whose scores lower than -30 kcal/mol were screened out from the database. These molecules were subjected to the second round of screening using amber score. Approximately 200 hit compounds with scores lower than -20 kcal/mol were analyzed and 4 of them were selected as lead compounds and then synthesized. The minimal inhibition concentrations (MICs) of the lead compounds were between 175-275 μg/mL, which were lower than that of Sulfadiazine (500 μg/mL) significantly. Meanwhile, these compounds were effective for both Gram-negative and Gram-positive bacteria. [Conclusion] The lead compounds had potential to become new antibacterial agents for conquering the drug resistance of P. aeruginosa.

    参考文献
    [1] Livermore DM. Has the era of untreatable infections arrived?. The Journal of Antimicrobial Chemotherapy, 2009, 64(Suppl 1): i29-i36.
    [2] Rice LB. The clinical consequences of antimicrobial resistance. Current Opinion in Microbiology, 2009, 12(5): 476-481.
    [3] Liu R, Luo BR, Li MY. Research progress of the resistant mechanisms of Pseudomonas aeruginosa to β-lactam antibiotics. International Journal of Laboratory Medicine, 2007, 28(8): 716-718. (in Chinese)刘蓉, 罗必蓉, 李明远. 铜绿假单胞菌对β-内酰胺类抗生素耐药机制研究进展. 国际检验医学杂志, 2007, 28(8): 716-718.
    [4] Wang LJ, Xu XL, Shi JR, Liu B, Sun HY, Bai YL, Ma CL. Research progress of multi-drug resistant Pseudomonas aeruginosa. International Journal of Laboratory Medicine, 2013, 34(13): 1713-1715. (in Chinese) 王丽娟, 徐修礼, 史皆然, 刘冰, 孙慧英, 白艳玲, 马春丽. 多药耐药铜绿假单胞菌研究进展. 国际检验医学杂志, 2013, 34(13): 1713-1715.
    [5] Bush K, Jacoby GA. Updated functional classification of β-lactamases. Antimicrobial Agents and Chemotherapy, 2010, 54(3): 969-976.
    [6] Korsak D, Markiewicz Z, Gutkind GO, Ayala JA. Identification of the full set of Listeria monocytogenes penicillin-binding proteins and characterization of PBPD2 (Lmo2812). BMC Microbiology, 2010, 10(1): 239.
    [7] Xie XS, Zhao YJ, Zhang DX, Du TT, Zhang B, Li J, Liu MC. Resistant mechanisms of Gram-negative bacteria to β-lactam antibiotics that mediated by PBPs. Chinese Journal of Preventive Veterinary Medicine, 2013, 35(2): 169-172. (in Chinese) 解晓双, 赵玉军, 张德显, 杜婷婷, 张冰, 李杰, 刘明春. PBPs介导革兰氏阴性菌对β-内酰胺类抗生素的耐药机制. 中国预防兽医学报, 2013, 35(2): 169-172.
    [8] Lim D, Strynadka NCJ. Structural basis for the β lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nature Structural & Molecular Biology, 2002, 9(11): 870-876.
    [9] Sainsbury S, Bird L, Rao V, Shepherd SM, Stuart DI, Hunter WN, Owens RJ, Ren JS. Crystal structures of penicillin-binding protein 3 from Pseudomonas aeruginosa: comparison of native and antibiotic-bound forms. Journal of Molecular Biology, 2011, 405(1): 173-184.
    [10] De León SR, Daniels K, Clarke AJ. Production and purification of the penicillin-binding protein 3 from Pseudomonas aeruginosa. Protein Expression and Purification, 2010, 73(2): 177-183.
    [11] Zhang C, Li WZ, Yun LH. Application of the combinatorial chemistry to research of the natural products. Progress in Chemistry, 2003, 15(3): 194-203. (in Chinese) 张城, 李伟章, 恽榴红. 用组合化学建立天然产物类似物库. 化学进展, 2003, 15(3): 194-203.
    [12] Kroemer RT. Structure-based drug design: docking and scoring. Current Protein & Peptide Science, 2007, 8(4): 312-328.
    [13] Song XR, Li D, Chen J, Zhao Y. Computer aided drug screening platform and its application. Chinese Journal of Bioinformatics, 2014, 12(4): 300-304. (in Chinese) 宋新蕊, 李达, 陈洁, 赵勇. 计算机辅助药物筛选平台及应用. 生物信息学, 2014, 12(4): 300-304.
    [14] Zervosen A, Sauvage E, Frère JM, Charlier P, Luxen A. Development of new drugs for an old target: the penicillin binding proteins. Molecules, 2012, 17(11): 12478-12505.
    [15] Hadizadeh F, Moradi A, Naghibi G, Vojdani M, Behravan J, Ramezani M. Synthesis and antitumor activity of substituted succinamides using a potato disc tumor induction assay. International Journal of Biomedical Science, 2007, 3(1): 60-64.
    [16] CLSI. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-ninth edition. CLSI document M07-A9. Wayne, PA: Clinical and Laboratory Standards Institute, 2012.
    [17] An YD, Du QZ, Tong LY, Yu ZW, Gong XW. Cloning, expression and purification of penicillin-binding protein 3 from Pseudomonas aeruginosa CMCC 10104. Protein Expression and Purification, 2015, 110: 37-42.
    [18] 李宇. 三苯基膦与碘温和活化下羧酸的酰胺化反应研究. 西南大学硕士学位论文, 2011.
    [19] Zhu W, Chen KJ, Xu XJ. Application of computerized virtual screening technique in traditional Chinese medicine. Chinese Journal of Integrated Traditional and Western Medicine, 2007, 27(3): 263-266. (in Chinese)朱伟, 陈可冀, 徐筱杰. 计算机药物虚拟筛选技术在中医药领域中的应用前景. 中国中西医结合杂志, 2007, 27(3): 263-266.
    [20] Xu J. A new approach to finding natural chemical structure classes. Journal of Medicinal Chemistry, 2002, 45(24): 5311-5320.
    [21] Koch MA, Waldmann H. Protein structure similarity clustering and natural product structure as guiding principles in drug discovery. Drug Discovery Today, 2005, 10(7): 471-483.
    [22] Luo XM, Jiang HL, Shen JH, Chen KX. The progress of drug design. Bulletin of Chinese Academy of Science, 2003, 18(4): 255-259. (in Chinese) 罗小民, 蒋华良, 沈建华, 陈凯先. 药物分子设计研究进展. 中国科学院院刊, 2003, 18(4): 255-259.
    [23] Xu WR, Tang LD, Fu HX, Liu BN, Liu P. Molecular simulation and virtual evaluation of new drugs. Chinese Pharmacologist, 2009, 26(2): 76. (in Chinese) 徐为人, 汤立达, 符海霞, 刘冰妮, 刘鹏. 分子模拟与新药虚拟评价. 中国药理通讯, 2009, 26(2): 76.
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喻召武,宋立华,童丽艳,王远,郑雯,宫兴文. 靶向铜绿假单胞菌(Pseudomonas aeruginosa)粘肽合成酶PBP3的抗菌先导化合物的虚拟筛选及活性研究[J]. 微生物学报, 2016, 56(2): 219-231

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  • 收稿日期:2015-05-18
  • 最后修改日期:2015-07-13
  • 在线发布日期: 2016-02-04
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