摘要
背景:抗生素耐药性目前是全球公共卫生的严重问题。为此,发现与新型靶标相互作用的新型抗菌药物很重要。脂蛋白的生物合成对细菌生存至关重要,其抑制剂已显示出对多种细菌的功效,因此细菌脂蛋白的生物合成途径是潜在的靶标。 方法:首先,综述了涵盖细菌脂蛋白生物合成途径的基本概念以及三种关键酶的生化特性的文献。然后,从蛋白质数据库(PDB)中检索了这三种酶最近解析的晶体结构,并分析了活性位点中的必需残基。最后,讨论了靶向该途径的所有可用特异性抑制剂及其结构活性关系(SAR)。 结果:我们简要介绍了细菌脂蛋白的生物合成途径,并详细描述了三种关键酶的结构和功能。此外,我们介绍了许多有关配体识别的知识,这些知识可能有助于基于结构的药物设计。此外,我们专注于LspA抑制剂的SAR,并讨论它们的效力和药物相似性。 结论:这篇综述提供了脂蛋白生物合成途径的清晰背景,并为基于结构的药物设计提供了实用的线索。特别是,针对靶向该途径的先导化合物的SAR的最新知识将为发现新型抗菌剂提供很好的参考。
关键词: 抗生素抗药性,细菌脂蛋白,Lgt,LspA,Lnt,球霉素,粘菌素,苯甲酰胺。
[http://dx.doi.org/10.1007/82_2016_492] [PMID: 27406189 ]
[http://dx.doi.org/10.1021/acsinfecdis.7b00084] [PMID: 28889735 ]
[http://dx.doi.org/10.1007/s00294-017-0703-x] [PMID: 28497241 ]
[http://dx.doi.org/10.1038/nrd4675] [PMID: 26493767 ]
[http://dx.doi.org/10.1128/ecosalplus.4.3.7] [PMID: 26443779 ]
[http://dx.doi.org/10.1126/science.aad3747] [PMID: 26912896 ]
[http://dx.doi.org/10.1038/ncomms10198] [PMID: 26729647 ]
[http://dx.doi.org/10.1128/IAI.00682-10] [PMID: 20974828 ]
[http://dx.doi.org/10.1073/pnas.74.3.1004] [PMID: 322142 ]
[http://dx.doi.org/10.1111/j.1365-2958.2010.07261.x] [PMID: 20572939 ]
[http://dx.doi.org/10.1016/j.bbalip.2016.11.009] [PMID: 27871940 ]
[http://dx.doi.org/10.1128/MMBR.00028-16] [PMID: 27512100 ]
[http://dx.doi.org/10.1128/JB.00314-12] [PMID: 22467779 ]
[http://dx.doi.org/10.1007/s00239-010-9334-2] [PMID: 20333370 ]
[http://dx.doi.org/10.1021/cr010166y] [PMID: 12475201 ]
[http://dx.doi.org/10.1016/j.pep.2012.11.001] [PMID: 23165241 ]
[http://dx.doi.org/10.1111/j.1574-6968.2001.tb10720.x] [PMID: 11425480 ]
[PMID: 6988430 ]
[PMID: 6368552 ]
[PMID: 2033085 ]
[PMID: 7040395 ]
[PMID: 8051048 ]
[http://dx.doi.org/10.1371/journal.pone.0041393] [PMID: 22911788 ]
[http://dx.doi.org/10.1128/JB.00127-12] [PMID: 22609911 ]
[http://dx.doi.org/10.1046/j.1365-2958.1999.01247.x] [PMID: 10096076 ]
[http://dx.doi.org/10.1021/pr400768v] [PMID: 24387739 ]
[http://dx.doi.org/10.1128/JB.177.23.6820-6824.1995] [PMID: 7592473 ]
[http://dx.doi.org/10.1128/JB.06641-11] [PMID: 22287519 ]
[http://dx.doi.org/10.1128/JB.179.9.2944-2948.1997] [PMID: 9139912 ]
[http://dx.doi.org/10.1111/febs.12041] [PMID: 23094979 ]
[http://dx.doi.org/10.1074/jbc.M307953200] [PMID: 12975369 ]
[http://dx.doi.org/10.1128/JB.00976-06] [PMID: 17041050 ]
[http://dx.doi.org/10.1111/j.1365-2958.2007.06065.x] [PMID: 18086214 ]
[http://dx.doi.org/10.1038/srep29495] [PMID: 27404047 ]
[PMID: 2985611 ]
[PMID: 1894646 ]
[http://dx.doi.org/10.1128/JB.181.18.5644-5651.1999] [PMID: 10482504 ]
[http://dx.doi.org/10.1074/jbc.274.40.28191] [PMID: 10497172 ]
[PMID: 3525566 ]
[http://dx.doi.org/10.1111/j.1574-6968.1991.tb04413.x] [PMID: 2032623 ]
[http://dx.doi.org/10.1128/JB.00099-07] [PMID: 17416655 ]
[http://dx.doi.org/10.1021/bi9020346] [PMID: 20000742 ]
[http://dx.doi.org/10.1074/jbc.M111.243519] [PMID: 21676878 ]
[http://dx.doi.org/10.1073/pnas.1707813114] [PMID: 28698362 ]
[http://dx.doi.org/10.1111/mmi.12897] [PMID: 25471278 ]
[http://dx.doi.org/10.1038/ncomms15948] [PMID: 28885614 ]
[http://dx.doi.org/10.1038/ncomms15952] [PMID: 28675161 ]
[http://dx.doi.org/10.1074/jbc.M207922200] [PMID: 12427759 ]
[http://dx.doi.org/10.1016/j.chembiol.2017.12.011] [PMID: 29337186 ]
[http://dx.doi.org/10.7164/antibiotics.31.410] [PMID: 670084 ]
[http://dx.doi.org/10.7164/antibiotics.31.421] [PMID: 353012 ]
[http://dx.doi.org/10.7164/antibiotics.31.426] [PMID: 670085 ]
[PMID: 3888977 ]
[http://dx.doi.org/10.1016/S0960-894X(03)00432-3] [PMID: 12824025 ]
[http://dx.doi.org/10.1021/ja002547j]
[http://dx.doi.org/10.1016/S0040-4020(03)00110-8]
[http://dx.doi.org/10.1021/jo1025145] [PMID: 21366318 ]
[http://dx.doi.org/10.1016/j.bmc.2003.10.055] [PMID: 14723954 ]
[http://dx.doi.org/10.1007/s13238-012-2023-8] [PMID: 22410786 ]
[http://dx.doi.org/10.1128/AAC.4.5.507] [PMID: 4208901 ]
[http://dx.doi.org/10.1139/m74-025] [PMID: 4362757 ]
[http://dx.doi.org/10.7164/antibiotics.35.788] [PMID: 6816780 ]
[http://dx.doi.org/10.7164/antibiotics.35.1454] [PMID: 6819280 ]
[http://dx.doi.org/10.1039/C39820001340]
[http://dx.doi.org/10.7164/antibiotics.37.13] [PMID: 6421789 ]
[http://dx.doi.org/10.7164/antibiotics.41.433] [PMID: 3131289 ]
[http://dx.doi.org/10.7164/antibiotics.41.439] [PMID: 3131290 ]
[http://dx.doi.org/10.1128/AAC.06148-11] [PMID: 22232277 ]
[http://dx.doi.org/10.1111/j.1600-051X.1989.tb01029.x] [PMID: 2613931 ]
[http://dx.doi.org/10.1111/j.1574-6968.2000.tb09365.x] [PMID: 11040435 ]
[http://dx.doi.org/10.1002/jlac.199419940712]
[http://dx.doi.org/10.1002/jlac.199419940713]
[http://dx.doi.org/10.1002/jlac.199419940714]
[http://dx.doi.org/10.1016/S0040-4039(00)77041-9]
[http://dx.doi.org/10.1002/chem.200700926] [PMID: 17768720 ]
[http://dx.doi.org/10.1021/jo00298a016]
[http://dx.doi.org/10.1016/S0960-894X(02)01024-7] [PMID: 12565921 ]
[http://dx.doi.org/10.1128/JB.01361-13] [PMID: 24391051 ]
[http://dx.doi.org/10.1038/ja.2017.30] [PMID: 28246379 ]
[http://dx.doi.org/10.1039/C7MD00528H] [PMID: 29527285 ]
[http://dx.doi.org/10.1038/nature22308] [PMID: 28489819 ]