Please wait a minute...
J Zhejiang Univ (Med Sci)  2019, Vol. 48 Issue (1): 44-49    DOI: 10.3785/j.issn.1008-9292.2019.02.08
    
New inhibitors targeting bacterial RNA polymerase
SHI Jing1(),FENG Jue1,2
Download: HTML( 16 )   PDF(1296KB)
Export: BibTeX | EndNote (RIS)      

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 wordsRifamycins/pharmacokinetics      Anti-bacterial agents      DNA-directed RNA polymerases/antagonists & inhibitors      Microscopy, electron      Freezing      Review     
Received: 25 July 2018      Published: 10 May 2019
CLC:  Q71  
Cite this article:

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

URL:

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


细菌RNA聚合酶抑制剂的分子生物学机制研究进展

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 
Figure 1 Structures of inhibitors in complex with bacterial RNA polymerase
Figure 2 Chemical structures of bacterial RNA polymerase inhibitors
[1]   GRUBER T M , GROSS C A . Multiple sigma subunits and the partitioning of bacterial transcription space[J]. Annu Rev Microbiol,2003,57:441-466.
[2]   ZHANG G , CAMPBELL E A , MINAKHIN L , et al . Crystal structure of thermus aquaticus core RNA polymerase at 3.3 ? resolution[J]. Cell,1999,98(6):811-824.
[3]   MURAKAMI K S . X-ray crystal structure of Escherichia coli RNA polymerase sigma70 holoenzyme[J]. J Biol Chem,2013,288(13):9126-9134.
[4]   DEGEN D , FENG Y , ZHANG Y , et al . Transcription inhibition by the depsipeptide antibiotic salinamide A[J/OL]. Elife,2014,3:e02451.
[5]   ZUO Y , WANG Y , STEITZ T A . The mechanism of E. coli RNA polymerase regulation by ppGpp is suggested by the structure of their complex[J]. Mol Cell,2013,50(3):430-436.
[6]   HUBIN E A , FAY A, XU C , et al . Structure and function of the mycobacterial transcription initiation complex with the essential regulator RbpA[J/OL]. Elife,2017,6:e22520.
[7]   LIN W , MANDAL S , DEGEN D , et al . Structural basis of mycobacterium tuberculosis transcription and transcription inhibition[J]. Mol Cell,2017,66(2):169-179.e8.
[8]   BAE B, DAVIS E , BROWN D , et al . Phage T7 Gp2 inhibition of Escherichia coli RNA polymerase involves misappropriation of sigma70 domain 1.1[J]. Proc Natl Acad Sci U S A,2013,110:19772-19777.
[9]   FEKLISTOV A , BAE B, HAUVER J , et al . RNA polymerase motions during promoter melting[J]. Science,2017,356(6340):863-866.
[10]   WEINZIERL R O . The nucleotide addition cycle of RNA polymerase is controlled by two molecular hinges in the bridge helix domain[J]. BMC Biol,2010,8:134.
[11]   HEIN P P , LANDICK R . The bridge helix coordinates movements of modules in RNA polymerase[J]. BMC Biol,2010,8:141.
[12]   WEHRLI W . Ansamycins chemistry, biosynthesis and biological activity[J]. Top Curr Chem,1977,72:21-49.
[13]   ROTHSTEIN D M . Rifamycins, alone and in combination[J]. Cold Spring Harb Perspect Med,2016,6(7):pii:a027011.
[14]   ARISTOFF P A , GARCIA G A , KIRCHHOFF P D , et al . Rifamycins—obstacles and opportunities[J]. Tuberculosis (Edinb),2010,90:94-118.
[15]   MOLODTSOV V , SCHARF N T , STEFAN M A , et al . Structural basis for rifamycin resistance of bacterial RNA polymerase by the three most clinically important RpoB mutations found in Mycobacterium tuberculosis [J]. Mol Microbiol,2017,103(6):1034-1045.
[16]   CAMPBELL E A , KORZHEVA N , MUSTAEV A , et al . Structural mechanism for rifampicin inhibition of bacterial RNA polymerase[J]. Cell,2001,104(6):901-912.
[17]   ARTSIMOVITCH I , VASSYLYEVA M N , SVETLOV D , et al . Allosteric modulation of the RNA polymerase catalytic reaction is an essential component of transcription control by rifamycins[J]. Cell,2005,122(3):351-363.
[18]   SMITH A B 3RD, DONG S , BRENNEMAN J B , et al . Total synthesis of (+)-sorangicin A[J]. J Am Chem Soc, 2009,131(34):12109-12111.
[19]   CAMPBELL E A , PAVLOVA O , ZENKIN N , et al . Structural, functional, and genetic analysis of sorangicin inhibition of bacterial RNA polymerase[J]. EMBO J,2005,24(4):674-682.
[20]   CICILIATO I , CORTI E , SARUBBI E , et al . Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase. I. Taxonomy, isolation and characterization[J]. J Antibiot (Tokyo),2004,57(3):210-217.
[21]   ZHANG Y , DEGEN D , HO M X, et al . GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides[J/OL]. Elife,2014,3:e02450.
[22]   MAFFIOLI S I , ZHANG Y , DEGEN D , et al . Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase[J]. Cell,2017,169(7):1240-1248.e23.
[23]   SIDDHIKOL C , ERBSTOESZER J W , WEISBLUM B . Mode of action of streptolydigin[J]. J Bacteriol,1969,99(1):151-155.
[24]   CASSANI G , BURGESS R R , GOODMAN H M , et al . Inhibition of RNA polymerase by streptolydigin[J]. Nat New Biol,1971,230(15):197-200.
[25]   MCCLURE W R . On the mechanism of streptolydigin inhibition of Escherichia coli RNA polymerase[J]. J Biol Chem,1980,255(4):1610-1616.
[26]   TEMIAKOV D , ZENKIN N , VASSYLYEVA M N , et al . Structural basis of transcription inhibition by antibiotic streptolydigin[J]. Mol Cell,2005,19(5):655-666.
[27]   TUSKE S , SARAFIANOS S G , WANG X , et al . Inhibition of bacterial RNA polymerase by streptolydigin: stabilization of a straight-bridge-helix active-center conformation[J]. Cell,2005,122(4):541-552.
[28]   MOORE B S , TRISCHMAN J A , SENG D , et al . Salinamides, antiinflammatory depsipeptides from a marine streptomycete[J]. J Org Chem,1999,64(4):1145-1150.
[29]   ARTSIMOVITCH I , CHU C , LYNCH A S , et al . A new class of bacterial RNA polymerase inhibitor affects nucleotide addition[J]. Science,2003,302(5645):650-654.
[30]   FENG Y , DEGEN D , WANG X , et al . Structural basis of transcription inhibition by CBR hydroxamidines and CBR pyrazoles[J]. Structure,2015,23(8):1470-1481.
[31]   IRSCHIK H , GERTH K , H?FLE G , et al . The myxopyronins, new inhibitors of bacterial RNA synthesis from Myxococcus fulvus (Myxobacterales)[J]. J Antibiot (Tokyo),1983,36(12):1651-1658.
[32]   MUKHOPADHYAY J , DAS K, ISMAIL S , et al . The RNA polymerase "switch region" is a target for inhibitors[J]. Cell,2008,135(2):295-307.
[33]   BELOGUROV G A , VASSYLYEVA M N , SEVOST-YANOVA A , et al . Transcription inactivation through local refolding of the RNA polymerase structure[J]. Nature,2009,457(7227):332-335.
[34]   MOLODTSOV V , FLEMING P R , EYERMANN C J , et al . X-ray crystal structures of Escherichia coli RNA polymerase with switch region binding inhibitors enable rational design of squaramides with an improved fraction unbound to human plasma protein[J]. J Med Chem,2015,58(7):3156-3171.
[35]   CHAKRABORTY A , WANG D , EBRIGHT Y W , et al . Opening and closing of the bacterial RNA polymerase clamp[J]. Science,2012,337(6094):591-595.
[36]   BUURMAN E T , FOULK M A , GAO N , et al . Novel rapidly diversifiable antimicrobial RNA polymerase switch region inhibitors with confirmed mode of action in Haemophilus influenzae[J]. J Bacteriol,2012,194(20):5504-5512.
[37]   LANCASTER J W , MATTHEWS S J . Fidaxomicin: the newest addition to the armamentarium against Clostridium difficile infections[J]. Clin Ther,2012,34(1):1-13.
[38]   VENUGOPAL A A , JOHNSON S . Fidaxomicin: a novel macrocyclic antibiotic approved for treatment of Clostridium difficile infection[J]. Clin Infect Dis,2012,54(4):568-574.
[39]   LIN W , DAS K, DEGEN D , et al . Structural basis of transcription inhibition by fidaxomicin (lipiarmycin A3)[J]. Mol Cell,2018,70(1):60-71.e15.
[1] Baboo Kalianee Devi, CHEN Zhengyun, ZHANG Xinmei. Progress on medical treatment in the management of adenomyosis[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 142-147.
[2] WU Binbin, YANG Yi. Biomarkers of cardiac surgery-associated acute kidney injury: a narrative review[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 224-229.
[3] YANG Kun, HU Xiaosheng. Research progress on miR-21 in heart diseases[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 214-218.
[4] XU Li, XU Ming, TONG Xiangmin. Effects of aerobic glycolysis on pathogenesis and drug resistance of non-Hodgkin lymphoma[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 219-223.
[5] ZHAO Shihao,ZHANG Xue,KE Yuehai. Progress on correlation between cell senescence and idiopathic pulmonary fibrosis[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 111-115.
[6] SONG Fangjun,GUO Hongtao. Progress on structural biology of voltage-gated ion channels[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 25-33.
[7] LI Chuntao,ZHANG Huibing,ZHANG Yan. Single-particle cryo-electron microscopy opens new avenues in structural biology of G protein-coupled receptor[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 39-43.
[8] SUN Boqiang,WANG Qiongyan,PAN Dongli. Mechanisms of herpes simplex virus latency and reactivation[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 89-101.
[9] SHEN Xiameng,LYU Weiguo. Research advances on the role of exosomes in chemotherapy resistance of ovarian cancer[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 116-120.
[10] HONG Feifan,LI Yuezhou. Application of mechanosensitive channels in sonogenetics[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 34-38.
[11] XIAO Li,TONG Xiaoyong. Advances in molecular mechanism of vascular remodeling in pulmonary arterial hypertension[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 102-110.
[12] XIANG Yilang,WU Ziheng,ZHANG Hongkun. Progress on in situ fenestration during thoracic endovascular aortic repair[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 617-622.
[13] CAO Liqin,SHI Jimin. Graft failure in allogeneic hematopoietic stem cell trans-plantation[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 651-658.
[14] TANG Hexiao,BAI Yuquan,SHEN Wulin,ZHAO Jinping. Research progress on interleukin-6 in lung cancer[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 659-664.
[15] ZHAO Huihui,TANG Huifang. Research progress on composite animal models of inflammatory bowel disease based on gene knockout[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 665-670.