结核分枝杆菌耐氟喹诺酮类药物的分子机制研究进展

doi:10.16288/j.yczz.16-136

遗传 ›› 2016, Vol. 38 ›› Issue (10): 918-927.doi: 10.16288/j.yczz.16-136

结核分枝杆菌耐氟喹诺酮类药物的分子机制研究进展

张玉娇, 李晓静, 米凯霞

中国科学院微生物研究所,病原微生物与免疫学重点实验室,北京 100101

收稿日期:2016-04-19 修回日期:2016-07-22 出版日期:2016-10-20 发布日期:2016-10-20
作者简介:米凯霞,博士,副研究员,研究方向：结核分枝杆菌耐药机制。
基金资助:
国家自然科学基金项目(编号：31270178,31670137)资助

Mechanisms of fluoroquinolone resistance in Mycobacterium tuberculosis

Yujiao Zhang, Xiaojing Li, Kaixia Mi

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China

Received:2016-04-19 Revised:2016-07-22 Online:2016-10-20 Published:2016-10-20
Supported by:
[Supported by the National Natural Science Foundation of China; (Nos; 31270178,31670137)]

摘要/Abstract

摘要： 结核病是由结核分枝杆菌(Mycobacterium tuberculosis)通过空气传播引起人类感染的慢性传染病,耐药结核分枝杆菌的流行是目前结核病防治的世界难题。氟喹诺酮类药物是人工合成药物,应用于耐药结核的临床治疗中,在治疗中起着核心的作用。但近年来,氟喹诺酮类药物的抗性菌株不断出现,愈发增加了结核病治疗的困难与治疗失败风险。在临床中氟喹诺酮药物的靶点比较清楚,是结核分枝杆菌的DNA旋转酶。目前发现结核分枝杆菌耐氟喹诺酮类药物的机制主要包括药物靶点DNA旋转酶的关键氨基酸改变、药物外排泵系统、细菌细胞壁厚度的增加以及喹诺酮抗性蛋白MfpA介导的DNA旋转酶活性调控。其中在氟喹诺酮靶标DNA旋转酶功能活性改变的耐药机制方面,编码DNA旋转酶基因突变一直是研究的热点,但近年来发现DNA旋转酶的调控蛋白MfpA以及DNA旋转酶的修饰在细菌耐药性中起着重要的作用,相关机制还亟待发现。本文综述了当前结核分枝杆菌耐氟喹诺酮类药物的作用机制,旨在为研发精准诊断技术和药物发掘提供科学理论基础和参考。

关键词: 结核分枝杆菌, 氟喹诺酮, 耐药, DNA旋转酶

Abstract: Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is one of the world’s deadliest bacterial infectious disease. It is still a global-health threat, particularly because of the drug-resistant forms. Fluoroquinolones, with target of gyrase, are among the drugs used to treat tuberculosis. However, their widespread use has led to bacterial resistance. The molecular mechanisms of fluoroquinolone resistance in mycobacterium tuberculosis have been reported, such as DNA gyrase mutations, drug efflux pumps system, bacterial cell wall thickness and pentapeptide proteins (MfpA) mediated regulation of gyrase. Mutations in gyrase conferring quinolone resistance play important roles and have been extensively studied. Recent studies have shown that the regulation of DNA gyrase affects mycobacterial drug resistance, but the mechanisms, especially by post-translational modification and regulatory proteins, are poorly understood. In this review, we summarize the fluoroquinolone drug development, and the molecular genetics of fluoroquinolone resistance in mycobacteria. Comprehensive understanding of the mechanisms of fluoroquinolone resistance in Mycobacterium tuberculosis will open a new view on understanding drug resistance in mycobacteria and lead to novel strategies to develop new accurate diagnosis methods.

Key words: Mycobacterium tuberculosis, fluoroquinolone, drug-resistance, DNA gyrase

张玉娇, 李晓静, 米凯霞. 结核分枝杆菌耐氟喹诺酮类药物的分子机制研究进展[J]. 遗传, 2016, 38(10): 918-927.

Yujiao Zhang, Xiaojing Li, Kaixia Mi. Mechanisms of fluoroquinolone resistance in Mycobacterium tuberculosis[J]. Hereditas(Beijing), 2016, 38(10): 918-927.

参考文献

[1] Ginsburg AS, Grosset JH, Bishai WR. Fluoroquinolones, tuberculosis, and resistance. Lancet Infect Dis , 2003, 3(7): 432-442.
[2] Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, van Soolingen D, Jensen P, Bayona J. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet , 2010, 375(9728): 1830-1843.
[3] Manjelievskaia J, Erck D, Piracha S, Schrager L. Drug- resistant TB: deadly, costly and in need of a vaccine. Trans Roy Soc Trop Med Hyg , 2016, 110(3): 186-191.
[4] Marks SM, Flood J, Seaworth B, Hirsch-Moverman Y, Armstrong L, Mase S, Salcedo K, Oh P, Graviss EA, Colson PW, Armitige L, Revuelta M, Sheeran K. Treatment practices, outcomes, and costs of multidrug-resistant and extensively drug-resistant tuberculosis, United States, 2005-2007. Emerg Infect Dis , 2014, 20(5): 812-821.
[5] O'Donnell MR, Jarand J, Loveday M, Padayatchi N, Zelnick J, Werner L, Naidoo K, Master I, Osburn G, Kvasnovsky C, Shean K, Pai M, Van der Walt M, Horsburgh CR, Dheda K. High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers. Ann Intern Med , 2010, 153(8): 516-522.
[6] Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, Grosset JH. Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother , 2008, 52(4): 1522-1524.
[7] Veziris N, Ibrahim M, Lounis N, Andries K, Jarlier V. Sterilizing activity of second-line regimens containing TMC207 in a murine model of tuberculosis. PLoS One , 2011, 6(3): e17556.
[8] Takiff H, Guerrero E. Current prospects for the fluoroquinolones as first-line tuberculosis therapy. Antimicrob Agents Chemother , 2011, 55(12): 5421-5429.
[9] An DD, Duyen NTH, Lan NTN, Hoa DV, Ha DTM, Kiet VS, Thu DDA, Van Vinh Chau N, Dung NH, Sy DN, Farrar J, Caws M. Beijing genotype of Mycobacterium tuberculosis is significantly associated with high-level fluoroquinolone resistance in Vietnam. Antimicrob Agents Chemother , 2009, 53(11): 4835-4839.
[10] Sun ZG, Zhang JY, Zhang XX, Wang SM, Zhang Y, Li CY. Comparison of gyrA gene mutations between laboratory-selected ofloxacin-resistant Mycobacterium tuberculosis strains and clinical isolates. Int J Antimicrob Agents , 2008, 31(2): 115-121.
[11] Lesher GY, Froelich EJ, Gruett MD, Bailey JH, Brundage RP. 1, 8-naphthyridine derivatives. A new class of chemotherapeutic agents. J Med Chem , 1962, 5(5): 1063-1065.
[12] Emmerson AM, Jones AM. The quinolones: decades of development and use. J Antimicrob Chemother , 2003, 51 (Suppl. 1): 13-20.
[13] Sullivan EA, Palumbo L, Ebrahimzadeh A, Frieden TR, Sullivan EA, Frieden TR, Kreiswirth BN, Kapur V, Musser JM. Emergence of fluoroquinolone-resistant tuberculosis in New York City. Lancet , 1995, 345(8958): 1148-1150.
[14] Ängeby KA, Jureen P, Giske CG, Chryssanthou E, Sturegård E, Nordvall M, Johansson AG, Werngren J, Kahlmeter G, Hoffner SE, Schön T. Wild-type MIC distributions of four fluoroquinolones active against Mycobacterium tuberculosis in relation to current critical concentrations and available pharmacokinetic and pharmacodynamic data. J Antimicrob Chemother , 2010, 65(5): 946-952.
[15] Shandil RK, Jayaram R, Kaur P, Gaonkar S, Suresh BL, Mahesh BN, Jayashree R, Nandi V, Bharath S, Balasubramanian V. Moxifloxacin, ofloxacin, sparfloxacin, and Ciprofloxacin rofloxacin against Mycobacterium tuberculosis : evaluation of in vitro and pharmacodynamic indices that best predict in vivo efficacy. Antimicrob Agents Chemother , 2007, 51(2): 576-582.
[16] Yadav V, Deopujari K. Gatifloxacin and dysglycemia in older adults. New Engl J Med , 2006, 354(25): 2725-2726.
[17] Renau TE, Gage JW, Dever JA, Roland GE, Joannides ET, Shapiro MA, Sanchez JP, Gracheck SJ, Domagala JM, Jacobs MR, Reynolds RC. Structure-activity relationships of quinolone agents against mycobacteria: effect of structural modifications at the 8 position. Antimicrob Agents Chemother , 1996, 40(10): 2363-2368.
[18] Mayer C, Takiff H. The molecular genetics of fluoroquinolone resistance in Mycobacterium tuberculosis . Microbiol Spectr , 2014, 2(4): 2-9.
[19] Espeli O, Levine C, Hassing H, Marians KJ. Temporal regulation of topoisomerase IV activity in E . coli . Mol Cell , 2003, 11(1): 189-201.
[20] Mdluli K, Ma ZK. Mycobacterium tuberculosis DNA gyrase as a target for drug discovery. Infect Disord Drug Targets , 2007, 7(2): 159-168.
[21] Forterre P, Gadelle D. Phylogenomics of DNA topoisomerases: their origin and putative roles in the emergence of modern organisms. Nucleic Acids Res , 2009, 37(3): 679-692.
[22] Wall MK, Mitchenall LA, Maxwell A. Arabidopsis thaliana DNA gyrase is targeted to chloroplasts and mitochondria. Proc Natl Acad Sci USA , 2004, 101(20): 7821-7826.
[23] Cho HS, Lee SS, Kim KD, Hwang I, Lim JS, Park YI, Pai HS. DNA gyrase is involved in chloroplast nucleoid partitioning. Plant Cell , 2004, 16(10): 2665-2682.
[24] Wang JC. Moving one DNA double helix through another by a type II DNA topoisomerase: the story of a simple molecular machine. Quart Rev Biophys , 1998, 31(2): 107- 144.
[25] Schoeffler AJ, Berger JM. DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Quart Rev Biophys , 2008, 41(1): 41-101.
[26] Hiasa H, Yousef DO, Marians KJ. DNA strand cleavage is required for replication fork arrest by a frozen topoisomerase-quinolone-DNA ternary complex. J Biol Chem , 1996, 271(42): 26424-26429.
[27] Takiff HE, Salazar L, Guerrero C, Philipp W, Huang WM, Kreiswirth B, Cole ST, Jacobs WR Jr, Telenti A. Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother , 1994, 38(4): 773-780.
[28] Yin XM, Yu ZX. Mutation characterization of gyrA and gyrB genes in levofloxacin-resistant Mycobacterium tuberculosis clinical isolates from Guangdong Province in China. J Infect , 2010, 61(2): 150-154.
[29] Lau RW, Ho PL, Kao RY, Yew WW, Lau TCK, Cheng VCC, Yuen KY, Tsui SKW, Chen XC, Yam WC. Molecular characterization of fluoroquinolone resistance in Mycobacterium tuberculosis : functional analysis of gyrA mutation at position 74. Antimicrob Agents Chemother , 2011, 55(2): 608-614.
[30] Aldred KJ, Blower TR, Kerns RJ, Berger JM, Osheroff N. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: enhancing drug activity against wild-type and resistant gyrase. Proc Natl Acad Sci USA , 2016, 113(7): E839-E846.
[31] Feng Y, Liu SJ, Wang QG, Wang L, Tang SW, Wang JM, Lu W. Rapid diagnosis of drug resistance to fluoroquinolones, amikacin, capreomycin, kanamycin and ethambutol using genotype MTBDRsl assay: a meta-analysis. PLoS One , 2013, 8(2): e55292.
[32] Kocagöz T, Hackbarth CJ, Unsal I, Rosenberg EY, Nikaido H, Chambers HF. Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra. Antimicrob Agents Chemother , 1996, 40(8): 1768-1774.
[33] Guillemin I, Jarlier V, Cambau E. Correlation between quinolone susceptibility patterns and sequences in the A and B subunits of DNA gyrase in mycobacteria. Antimicrob Agents Chemother , 1998, 42(8): 2084-2088.
[34] Cui ZL, Wang J, Lu JM, Huang XC, Hu ZY. Association of mutation patterns in gyrA/B genes and ofloxacin resistance levels in Mycobacterium tuberculosis isolates from East China in 2009. BMC Infect Dis , 2011, 11: 78.
[35] Malik S, Willby M, Sikes D, Tsodikov OV, Posey JE. New insights into fluoroquinolone resistance in Mycobacterium tuberculosis : functional genetic analysis of gyrA and gyrB mutations. PLoS One , 2012, 7(6): e39754.
[36] Pantel A, Petrella S, Veziris N, Brossier F, Bastian S, Jarlier V, Mayer C, Aubry A. Extending the definition of the GyrB quinolone resistance-determining region in Mycobacterium tuberculosis DNA gyrase for assessing fluoroquinolone resistance in M . tuberculosis . Antimicrob Agents Chemother , 2012, 56(4): 1990-1996.
[37] Sulochana S, Narayanan S, Paramasivan CN, Suganthi C, Narayanan PR. Analysis of fluoroquinolone resistance in clinical isolates of Mycobacterium tuberculosis from India. J Chemother , 2007, 19(2): 166-171.
[38] Cheng AFB, Yew WW, Chan EWC, Chin ML, Hui MMM, Chan RCY. Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother , 2004, 48(2): 596-601.
[39] Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev , 2006, 19(2): 382-402.
[40] Colangeli R, Helb D, Sridharan S, Sun JC, Varma-Basil M, Hazbón MH, Harbacheuski R, Megjugorac NJ, Jacobs WR Jr, Holzenburg A, Sacchettini JC, Alland D. The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drug tolerance to both isoniazid and ethambutol. Mol Microbiol , 2005, 55(6): 1829-1840.
[41] De Rossi E, Aínsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol Rev , 2006, 30(1): 36-52.
[42] Vilchèze C, Wang F, Arai M, Hazbón MH, Colangeli R, Kremer L, Weisbrod TR, Alland D, Sacchettini JC, Jacobs WR Jr. Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. Nat Med , 2006, 12(9): 1027-1029.
[43] Liu J, Takiff HE, Nikaido H. Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump. J Bacteriol , 1996, 178(13): 3791- 3795.
[44] De Rossi E, Arrigo P, Bellinzoni M, Silva PA, Martín C, Aínsa JA, Guglierame P, Riccardi G. The multidrug transporters belonging to major facilitator superfamily in Mycobacterium tuberculosis . Mol Med , 2002, 8(11): 714-724.
[45] Zhang CY, Feng YX, Li P, Fu SB. Study on the relationship between the resistance to MTX and the transport protein superfamily of ATP-binding cassette that induces multiple drug resistance. Hereditas (Beijing) , 2006, 28(10): 1201-1205. 张春玉, 冯源熙, 李璞, 傅松滨. 介导多药耐药的ABC转运蛋白超家族与MTX耐药性的关系研究. 遗传, 2006, 28(10): 1201-1205.
[46] Choudhuri BS, Bhakta S, Barik R, Basu J, Kundu M, Chakrabarti P. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis . Biochem J , 2002, 367(Pt 1): 279-285.
[47] Banerjee SK, Bhatt K, Misra P, Chakraborti PK. Involvement of a natural transport system in the process of efflux-mediated drug resistance in Mycobacterium smegmatis . Mol Gen Genet , 2000, 262(6): 949-956.
[48] Siroy A, Mailaender C, Harder D, Koerber S, Wolschendorf F, Danilchanka O, Wang Y, Heinz C, Niederweis M. Rv1698 of Mycobacterium tuberculosis represents a new class of channel-forming outer membrane proteins. J Biol Chem , 2008, 283(26): 17827-17837.
[49] Velayati AA, Farnia P, Ibrahim TA, Haroun RZ, Kuan HO, Ghanavi J, Farnia P, Kabarei AN, Tabarsi P, Omar AR, Varahram M, Masjedi MR. Differences in cell wall thickness between resistant and nonresistant strains of Mycobacterium tuberculosis : using transmission electron microscopy. Chemotherapy , 2009, 55(5): 303-307.
[50] Tao J, Han J, Wu HY, Hu XL, Deng JY, Fleming J, Maxwell A, Bi LJ, Mi KX. Mycobacterium fluoroquinolone resistance protein B, a novel small GTPase, is involved in the regulation of DNA gyrase and drug resistance. Nucleic Acids Res , 2013, 41(4): 2370-2381.
[51] Sengupta S, Shah M, Nagaraja V. Glutamate racemase from Mycobacterium tuberculosis inhibits DNA gyrase by affecting its DNA-binding. Nucleic Acids Res , 2006, 34(19): 5567-5576.
[52] Montero C, Mateu G, Rodriguez R, Takiff H. Intrinsic resistance of Mycobacterium smegmatis to fluoroquinolones may be influenced by new pentapeptide protein MfpA. Antimicrob Agents Chemother , 2001, 45(12): 3387-3392.
[53] Hegde SS, Vetting MW, Roderick SL, Mitchenall LA, Maxwell A, Takiff HE, Blanchard JS. A fluoroquinolone resistance protein from Mycobacterium tuberculosis that mimics DNA. Science , 2005, 308(5727): 1480-1483.
[54] Jacoby GA, Hooper DC. Phylogenetic analysis of chromosomally determined qnr and related proteins. Antimicrob Agents Chemother , 2013, 57(4): 1930-1934.
[55] Tran JH, Jacoby GA, Hooper DC. Interaction of the plasmid- encoded quinolone resistance protein Qnr with Escherichia coli DNA gyrase. Antimicrob Agents Chemother , 2005, 49(1): 118-125.
[56] Mérens A, Matrat S, Aubry A, Lascols C, Jarlier V, Soussy CJ, Cavallo JD, Cambau E. The pentapeptide repeat proteins MfpA Mt and QnrB4 exhibit opposite effects on DNA gyrase catalytic reactions and on the ternary gyrase-DNA- quinolone complex. J Bacteriol , 2009, 191(5): 1587-1594.
[57] Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science , 2009, 325(5942): 834-840.
[58] Mao Y, Sun M, Desai SD, Liu LF. SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci USA , 2000, 97(8): 4046-4051.
[59] Harms A, Stanger FV, Scheu PD, De Jong IG, Goepfert A, Glatter T, Gerdes K, Schirmer T, Dehio C. Adenylylation of gyrase and topo IV by FicT toxins disrupts bacterial DNA Topology. Cell Rep , 2015, 12(9): 1497-1507.

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