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浙江大学学报（医学版）
浙江大学学报（医学版）  2019, Vol. 48 Issue (1): 44-49    DOI: 10.3785/j.issn.1008-9292.2019.02.08
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细菌RNA聚合酶抑制剂的分子生物学机制研究进展
史婧1(),冯钰1,2
1. 浙江大学医学院生物物理系， 浙江 杭州 310058
2. 浙江大学医学院附属邵逸夫医院病理科， 浙江 杭州 310016
New inhibitors targeting bacterial RNA polymerase
SHI Jing1(),FENG Jue1,2
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摘要：

细菌RNA聚合酶抑制剂利福霉素类药物是治疗结核病的一线药物，随着利福霉素类药物耐药菌的出现，开发能杀灭利福霉素类药物耐药菌且生物利用度高的新型RNA聚合酶抑制剂已迫在眉睫。细菌RNA聚合酶与不同抑制剂复合物的晶体结构和冷冻电镜结构研究揭示了RNA聚合酶抑制剂主要具有以下分子生物学作用机制：①阻止短RNA延伸；②与底物竞争；③阻止“桥螺旋”变构；④阻止蟹钳打开；⑤阻止蟹钳关闭。本文综述了这五类重要RNA聚合酶抑制剂的研究进展，以期为已有RNA聚合酶抑制剂的修饰改造和新型RNA聚合酶抑制剂的开发提供参考。
关键词： 利福霉素类/药代动力学;  抗菌药;  指导DNA的RNA聚合酶类/拮抗剂和抑制剂;  显微镜检查，电子;  冷冻;  综述    
Abstract:

Rifamycins, a group of bacterial RNA polymerase inhibitors, are the first-line antimicrobial drugs to treat tuberculosis. In light of the emergence of rifamycin-resistant bacteria, development of new RNA polymerase inhibitors that kill rifamycin-resistant bacteria with high bioavailability is urgent. Structural analysis of bacterial RNA polymerase in complex with inhibitors by crystallography and cryo-EM indicates that RNA polymerase inhibitors function through five distinct molecular mechanisms: inhibition of the extension of short RNA; competition with substrates; inhibition of the conformational change of the ‘bridge helix’; inhibition of clamp opening； inhibition of clamp closure. This article reviews the research progress of these five groups of RNA polymerase inhibitors to provide references for the modification of existing RNA polymerase inhibitors and the discovery of new RNA polymerase inhibitors.
Key words: Rifamycins/pharmacokinetics    Anti-bacterial agents    DNA-directed RNA polymerases/antagonists & inhibitors    Microscopy, electron    Freezing    Review
收稿日期: 2018-07-25 出版日期: 2019-05-10
:  Q71  
基金资助: 国家重点研发计划(2018YFA0507800)
作者简介: 史　婧（1981—），女，博士，助理研究员，讲师，主要从事细菌RNA聚合酶的结构及功能研究；E-mail: 0617440@zju.edu.cn; https://orcid.org/0000-0001-9389-4055
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史婧,冯钰. 细菌RNA聚合酶抑制剂的分子生物学机制研究进展[J]. 浙江大学学报（医学版）, 2019, 48(1): 44-49.

SHI Jing,FENG Jue. New inhibitors targeting bacterial RNA polymerase. J Zhejiang Univ (Med Sci), 2019, 48(1): 44-49.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2019.02.08    或    http://www.zjujournals.com/med/CN/Y2019/V48/I1/44

图1  细菌RNA聚合酶和抑制剂的复合物结构
图2  细菌RNA聚合酶抑制剂的化学结构
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