六、小结
结核分枝杆菌是一种古老的物种，尽管这么多年过去人类对于它的认识在不断地进步，但是还存在显著的不足。对于结核病的治疗尽管已经有了很多的治疗药物，但是即便类似贝达喹啉、利奈唑胺等新型的抗TB药物也已经有一定的耐药发生。2014年5月，世界卫生大会批准实现“到2035年结束全球结核病流行”的宏伟目标，而这一目标的实现需要更好的抗菌药物管理策略，需要政府负责管理和问责，需要全社会和民间组织的共同参与，需要尊重人权、道德与公平，需要适应本地化、本土化条件。基于这些目标，目前已经有很多检测方法可以用于识别和临床判定分离菌株的耐药情况。临床一线工作人员也有必要对常用药物和其耐药机制加以简单的了解。本章限于篇幅仅做了一些基本的介绍，难免有不足之处，请读者指正。
（周 密）
参考文献
1.Pai M , Behr MA , Dowdy D , et al.Tuberculosis［J］.Nature Reviews Disease Primers.2016; 2(3): 16076.
2.Daniels M, Hill AB.Chemotherapy of pulmonary tuberculosis in young adults; an analysis of the combined results of three Medical Research Council trials［J］.British medical journal.1952; 1(4769): 1162—1168.
3.WHO.Global tuberculosis report［EB/OL］ .Geneva: WHO.2018.
4.Tao NN, He XC, Zhang XX, Liu Y, Yu CB, Li HC.Drug-Resistant Tuberculosis among Children, China, 2006—2015［J］.Emerging infectious diseases.2017; 23(11): 1800—1805.
5.National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.TB Elimination Multidrug-Resistant Tuberculosis (MDR TB) 2016［EB/OL］.Available from: https://www.cdc.gov/tb/publications/factsheets/drtb/mdrtb.htm.
6.Nguyen L.Antibiotic resistance mechanisms in M.tuberculosis: an update［J］.Archives of toxicology.2016; 90(7): 1585—1604.
7.梅建，薛桢，沈鑫，等.原发性耐药是耐药结核病产生的重要原因［J］.中华结核和呼吸杂志，2006；29（2）：75—78.
8.Van Rie A, Warren R, Richardson M, et al.Classification of drug-resistant tuberculosis in an epidemic area［J］.Lancet.2000; 356(9223): 22—25.
9.高谦，梅建.传播才是造成我国结核病高耐药率的主要原因［J］.中国防痨杂志，2015；37（11）：1091—1096.
10.Schon T, Miotto P, Koser CU, Viveiros M, Bottger E, Cambau E.Mycobacterium tuberculosis drug-resistance testing: challenges, recent developments and perspectives［J］.Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.2017; 23(3): 154—160.
11.Zhang Y, Yew WW.Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015［J］.The international journal of tuberculosis and lung disease : the oき cial journal of the International Union against Tuberculosis and Lung Disease.2015; 19(11): 1276—1289.
12.Hameed HMA, Islam MM, Chhotaray C, et al.Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains［J］.Frontiers in cellular and infection microbiology.2018; 8(4): 114.
13.Xu Y, Zhang Z, Sun Z.Drug resistance to Mycobacterium tuberculosis: from the traditional Chinese view to modern systems biology［J］.Critical reviews in microbiology.2015; 41(3):399—410.
14.Gygli SM, Borrell S, Trauner A, Gagneux S.Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives［J］.FEMS microbiology reviews.2017; 41(3): 354—373.
15.Le Chevalier F, Cascioferro A, Majlessi L, Herrmann JL, Brosch R.Mycobacterium tuberculosis evolutionary pathogenesis and its putative impact on drug development［J］.Future microbiology.2014; 9(8): 969—985.(https://www.daowen.com)
16.Kaur D, Guerin ME, Skovierova H, Brennan PJ, Jackson M.Chapter 2: Biogenesis of the cell wall and other glycoconjugates of Mycobacterium tuberculosis［J］.Advances in applied microbiology.2009; 69(2): 23—78.
17.Zuber B, Chami M, Houssin C, et al.Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state［J］.Journal of bacteriology.2008;190(16): 5672—5680.
18.Velayati AA, Farnia P, Ibrahim TA, et al.Differences in cell wall thickness between resistant and nonresistant strains of Mycobacterium tuberculosis: using transmission electron microscopy［J］.Chemotherapy.2009; 55(5): 303—307.
19.Wang F, Cassidy C, Sacchettini JC.Crystal structure and activity studies of the Mycobacterium tuberculosis beta-lactamase reveal its critical role in resistance to betalactam antibiotics［J］.Antimicrobial agents and chemotherapy.2006; 50(8): 2762—2771.
20.Hugonnet JE, Blanchard JS.Irreversible inhibition of the Mycobacterium tuberculosis betalactamase by clavulanate［J］.Biochemistry.2007; 46(43): 11998—12004.
21.Cohen KA, El-Hay T, Wyres KL, et al.Paradoxical Hypersusceptibility of Drug-resistant Mycobacteriumtuberculosis to beta-lactam Antibiotics［J］.EBioMedicine.2016; 9(7): 170—179.
22.Warrier T, Kapilashrami K, Argyrou A, et al.N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis［J］.Proceedings of the National Academy of Sciences of the United States of America.2016; 113(31): E4523—4530.
23.Warrier T, Martinez-Hoyos M, Marin-Amieva M, et al.Identification of Novel Antimycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium tuberculosis［J］.ACS infectious diseases.2015; 1(12):580—585.
24.Buriankova K, Doucet-Populaire F, Dorson O, et al.Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex［J］.Antimicrobial agents and chemotherapy.2004; 48(1): 143—150.
25.Madsen CT, Jakobsen L, Buriankova K, et al.Methyltransferase Erm(37) slips on rRNA to confer atypical resistance in Mycobacterium tuberculosis［J］.The Journal of biological chemistry.2005; 280(47): 38942—38947.
26.Sandgren A, Strong M, Muthukrishnan P, et al.Tuberculosis drug resistance mutation database［J］.PLoS medicine.2009; 6(2): e2.
27.Rautio J, Meanwell N, Di Li, et al.The expanding role of prodrugs in contemporary drug design and development［J］.Nature Reviews Drug Discovery.2018; 17(8): 559—587.
28.Desjardins CA, Cohen KA, Munsamy V, et al.Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance［J］.Nature genetics.2016; 48(5): 544—551.
29.Boshoff HI, Reed MB, Barry CE, et al.Polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis［J］.Cell.2003; 113(2): 183—193.
30.O’Sullivan DM, Hinds J, Butcher PD, et al.Mycobacterium tuberculosis DNA repair in response to subinhibitory concentrations of ciprofloxacin［J］.The Journal of antimicrobial chemotherapy.2008; 62(6): 1199—1202.
31.Gorna AE, Bowater RP, Dziadek J.DNA repair systems and the pathogenesis of Mycobacterium tuberculosis: varying activities at different stages of infection［J］.Clinical science.2010; 119(5): 187—202.
32.Provvedi Roberta, Boldrin Francesca, Falciani Francesco, et al.Global transcriptional response to vancomycin in Mycobacterium tuberculosis ［J］.Microbiology.2009; 155(Pt 4):1093—1102.
33.Beste D.J., McFadden J.System-level strategies for studying the metabolism of Mycobacterium tuberculosis［J］.Molecular bioSystems.2010; 6(12): 2363—2372.