Mechanisms of drug resistance in Mycobacterium tuberculosis: Update 2015

International Journal of Tuberculosis and Lung Disease

Volumn 19, Issue 11, 2015, Pages 1276-1289

  Zhang, Y ^a   Yew, W W ^b  

^a JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

^b CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

Antibiotics; Drug resistance; Mechanisms; Molecular diagnostics; New drugs

Indexed keywords

AMIKACIN; AMINOGLYCOSIDE ANTIBIOTIC AGENT; AMINOSALICYLIC ACID; BEDAQUILINE; CAPREOMYCIN; CLOFAZIMINE; CYCLOSERINE; DELAMANID; ETHAMBUTOL; ETHIONAMIDE; GATIFLOXACIN; ISONIAZID; KANAMYCIN; LINEZOLID; N (2 ADAMANTYL) N' GERANYLETHYLENEDIAMINE; PRETOMANID; PROTIONAMIDE; PYRAZINAMIDE; QUINOLINE DERIVED ANTIINFECTIVE AGENT; RIFAMPICIN; STREPTOMYCIN; TERIZIDONE; TUBERCULOSTATIC AGENT; VIOMYCIN;

ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; ANTIBIOTIC SENSITIVITY; BACTERIAL MUTATION; BACTERIAL VIRULENCE; BACTERICIDAL ACTIVITY; DRUG APPROVAL; DRUG EFFICACY; DRUG MEGADOSE; DRUG REPOSITIONING; DRUG RESISTANT TUBERCULOSIS; DRUG TOLERANCE; DRUG TREATMENT FAILURE; EXTENSIVELY DRUG RESISTANT TUBERCULOSIS; GENE MUTATION; GENETIC RESISTANCE; HUMAN; META ANALYSIS (TOPIC); MINIMUM INHIBITORY CONCENTRATION; MOLECULAR DIAGNOSIS; MULTIDRUG RESISTANT TUBERCULOSIS; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; OUTCOME ASSESSMENT; PERSONALIZED MEDICINE; PHARMACODYNAMICS; PRIORITY JOURNAL; REVIEW; SEQUENCE ANALYSIS; TREATMENT DURATION; TUBERCULOSIS CONTROL; CLASSIFICATION; DRUG DESIGN; DRUG EFFECTS; GENETICS; MULTIDRUG RESISTANCE; TUBERCULOSIS, MULTIDRUG-RESISTANT;

ANTITUBERCULAR AGENTS; DRUG DESIGN; DRUG RESISTANCE, MULTIPLE, BACTERIAL; HUMANS; MYCOBACTERIUM TUBERCULOSIS; TUBERCULOSIS, MULTIDRUG-RESISTANT;

EID: 84945587445     PISSN: 10273719     EISSN: 18157920     Source Type: Journal    
DOI: 10.5588/ijtld.15.0389     Document Type: Review

References (155)

1. McDermott W. Antimicrobial therapy of pulmonary tuberculosis. Bull World Health Organ 1960; 23: 427-461.
2. World Health Organization. Global tuberculosis report, 2014. WHO/HTM/TB/2014.08. Geneva, Switzerland: WHO, 2014.
3. Dean A S, Zignol M, Falzon D, Getahun H, Floyd K. HIV and multidrug-resistant tuberculosis: overlapping epidemics. Eur Respir J 2014; 44: 251-254.
4. Zhang Y, Yew W W. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009; 13: 1320-1330.
5. Zhang Y, Yew W W, Barer M R. Targeting persisters for tuberculosis control. Antimicrob Agents Chemother 2012; 56: 2223-2230.
6. Zhang Y. Persisters, persistent infections and the Yin-Yang Model. Emerg Microb Infect 2014; 3: e3.
7. Jiang X, Zhang W, Zhang Y, et al. Assessment of efflux pump gene expression in a clinical isolate Mycobacterium tuberculosis by real-time reverse transcription PCR. Microb Drug Resist 2008; 14: 7-11.
8. Rodrigues L, Machado D, Couto I, Amaral L, Viveiros M. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect Genet Evol 2012; 12: 695-700.
9. Pasipanodya J G, Gumbo T. A new evolutionary and pharmacokinetic-pharmacodynamic scenario for rapid emergence of resistance to single and multiple antituberculosis drugs. Curr Opin Pharmacol 2011; 11: 457-463.
10. Suchindran S, Brouwer E S, Van Rie A. Is HIV infection a risk factor for multi-drug resistant tuberculosis? A systematic review. PLOS ONE 2009; 4 e5561.
11. Mesfin Y M, Hailemariam D, Biadgilign S, Kibret K T. Association between HIV/AIDS and multi-drug resistance tuberculosis: a systematic review and meta-analysis. PLOS ONE 2014; 9: e82235.
12. Zhao Y, Xu S,Wang L, et al. National survey of drug-resistant tuberculosis in China. N Engl J Med 2012; 366: 2161-2170.
13. Otero L, Krapp F, Tomatis C, et al. High prevalence of primary multidrug resistant tuberculosis in persons with no known risk factors. PLOS ONE 2011; 6: e26276.
14. Bantubani N, Kabera G, Connolly C, et al. High rates of potentially infectious tuberculosis and multidrug-resistant tuberculosis (MDR-TB) among hospital inpatients in KwaZulu Natal, South Africa indicate risk of nosocomial transmission. PLOS ONE 2014; 9: e90868.
15. Zhang Y, Chang K, Leung C, et al. 'ZS-MDR-TB' versus 'ZRMDR TB': improving treatment of MDR-TB by identifying pyrazinamide susceptibility. Emerg Microbes Infect 2012; 1: e5.
16. Chang K C, Leung C C, Yew W W, et al. Pyrazinamide may improve fluoroquinolone-based treatment of multidrugresistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5465-5475.
17. Dalton T, Cegielski P, Akksilp S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012; 380: 1406-1417.
18. Ershova J V, Kurbatova E V, Moonan P K, Cegielski J P. Acquired resistance to second-line drugs among persons with tuberculosis in the United States. Clin Infect Dis 2012; 55: 1600-1607.
19. Ershova J V, Kurbatova E V, Moonan P K, Cegielski J P. Mortality among tuberculosis patients with acquired resistance to second-line antituberculosis drugs-United States, 1993-2008. Clin Infect Dis 2014; 59: 465-472.
20. Falzon D, Gandhi N, Migliori G B, et al. Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J 2013; 42: 156 168.
21. Migliori G B, Sotgiu G, Gandhi N R, et al. Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 2013; 42: 169-179.
22. Aung K J, Van Deun A, Declercq E, et al. Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014; 18: 1180-1187.
23. Zhang Y, Heym B, Allen B, Young D, Cole S. The catalaseperoxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 1992; 358: 591-593.
24. Zhang Y, Telenti A. Genetics of drug resistance in Mycobacterium tuberculosis. Hatfull G, Jacobs W R, ed. Washington, DC, USA: ASM Press, 2000: pp 235-254.
25. Rozwarski D A, Grant G A, Barton D H, Jacobs W R, Jr, Sacchettini J C. Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 1998; 279: 98-102.
26. Niki M, Tateishi Y, Ozeki Y, et al. A novel mechanism of growth phase-dependent tolerance to isoniazid in mycobacteria. J Biol Chem 2012; 287: 27 743-27 752.
27. Hazbon M H, Brimacombe M, Bobadilla del Valle M, et al. Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2006; 50: 2640-2649.
28. Ando H, Kitao T, Miyoshi-Akiyama T, Kato S, Mori T, Kirikae T. Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis. Mol Microbiol 2011; 79: 1615-1628.
29. Siu G K, YamWC, Zhang Y, Kao RY. An upstream truncation of the furA-katG operon confers high-level isoniazid resistance in a Mycobacterium tuberculosis clinical isolate with no known resistance-associated mutations. Antimicrob Agents Chemother 2014; 58: 6093-6100.
30. Banerjee A, Dubnau E, Quemard A, et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 1994; 263: 227-230.
31. Campbell P J, Morlock G P, Sikes R D, et al. Molecular detection of mutations associated with first- and second-line drug resistance compared with conventional drug susceptibility testing of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2011; 55: 2032-2041.
32. Guo H, Seet Q, Denkin S, Parsons L, Zhang Y. Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA. J Med Microbiol 2006; 55: 1527-1531.
33. Shekar S, Yeo Z X, Wong J C, et al. Detecting novel genetic variants associated with isoniazid-resistant Mycobacterium tuberculosis. PLOS ONE 2014; 9: e102383.
34. Wilson T M, de Lisle G W, Collins D M. Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis. Mol Microbiol 1995; 15: 1009-1015.
35. Zhang Y, Shi W, Zhang W, Mitchison D. Mechanisms of pyrazinamide action and resistance. Microbiol Spectr 2013; 2: 1-12.
36. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis 2003; 7: 6-21.
37. Scorpio A, Zhang Y. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nat Med 1996; 2: 662-667.
38. Zhang Y, Wade M M, Scorpio A, Zhang H, Sun Z. Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother 2003; 52: 790-795.
39. Shi W, Zhang X, Jiang X, et al. Pyrazinamide inhibits transtranslation in Mycobacterium tuberculosis. Science 2011; 333: 1630-1632.
40. Zhang S, Chen J, ShiW, LiuW, ZhangW, Zhang Y. Mutations in panD encoding aspartate decarboxylase are associated with pyrazinamide resistance in Mycobacterium tuberculosis. Emerg Microbes Infect 2013; 2: e34.
41. ShiW, Chen J, Feng J, et al. Aspartate decarboxylase (PanD) as a new target of pyrazinamide in Mycobacterium tuberculosis. Emerg Microbes Infect 2014; 3: e58.
42. Scorpio A, Lindholm-Levy P, Heifets L, et al. Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 1997; 41: 540 543.
43. Cheng S J, Thibert L, Sanchez T, Heifets L, Zhang Y. pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada. Antimicrob Agents Chemother 2000; 44: 528-532.
44. Sreevatsan S, Pan X, Zhang Y, Kreiswirth B N, Musser J M. Mutations associated with pyrazinamide resistance in pncA of Mycobacterium tuberculosis complex organisms. Antimicrob Agents Chemother 1997; 41: 636-640.
45. Hirano K, Takahashi M, Kazumi Y, Fukasawa Y, Abe C. Mutation in pncA is a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis. Tubercle Lung Dis 1997; 78: 117-122.
46. Morlock G P, Crawford J T, Butler W R, et al. Phenotypic characterization of pncA mutants of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2000; 44: 2291-2295.
47. Jureen P, Werngren J, Toro J C, Hoffner S. Pyrazinamide resistance and pncA gene mutations in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2008; 52: 1852-1854.
48. Feuerriegel S, Koser C U, Richter E, Niemann S. Mycobacterium canettii is intrinsically resistant to both pyrazinamide and pyrazinoic acid. J Antimicrob Chemother 2013; 68: 1439-1440.
49. Somoskovi A, Dormandy J, Parsons L M, et al. Sequencing of the pncA gene in members of the Mycobacterium tuberculosis complex has important diagnostic applications: identification of a species-specific pncA mutation in 'Mycobacterium canettii' and the reliable and rapid predictor of pyrazinamide resistance. J Clin Microbiol 2007; 45: 595-599.
50. Simons S O, van Ingen J, van der Laan T, et al. Validation of pncA gene sequencing in combination with the MGIT method to test susceptibility of Mycobacterium tuberculosis to pyrazinamide. J Clin Microbiol 2012; 50: 428-434.
51. Chedore P, Bertucci L, Wolfe J, Sharma M, Jamieson F. Potential for erroneous results indicating resistance when using the BACTECe MGITe 960 system for testing susceptibil ity of Mycobacterium tuberculosis to pyrazinamide. J Clin Microbiol. 2010; 48: 300-301.
52. Dormandy J, Somoskovi A, Kreiswirth B N, Driscoll J R, Ashkin D, Salfinger M. Discrepant results between pyrazinamide susceptibility testing by the reference BACTEC 460TB method and pncA DNA sequencing in patients infected with multidrug-resistant W-Beijing Mycobacterium tuberculosis strains. Chest 2007; 131: 497-501.
53. Miotto P, Cabibbe A M, Feuerriegel S, et al. Mycobacterium tuberculosis pyrazinamide resistance determinants: a multicenter study. MBio 2014; 5: e01819-14.
54. Hoffner S, Angeby K, Sturegard E, et al. Proficiency of drug susceptibility testing of Mycobacterium tuberculosis against pyrazinamide: the Swedish experience. Int J Tuberc Lung Dis 2013; 17: 1486-1490.
55. Yee D P, Menzies D, Brassard P. Clinical outcomes of pyrazinamide-monoresistant Mycobacterium tuberculosis in Quebec. Int J Tuberc Lung Dis 2012; 16: 604-609.
56. Piccaro G, Pietraforte D, Giannoni F, Mustazzolu A, Fattorini L. Rifampin induces hydroxyl radical formation in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2014; 58: 7527-7533.
57. de Steenwinkel J E, ten Kate M T, et al. Drug susceptibility of Mycobacterium tuberculosis Beijing genotype and association with MDR-TB. Emerg Infect Dis 2012; 18: 660-663.
58. den Hertog A L, Menting S, van Soolingen D, Anthony R M. Mycobacterium tuberculosis Beijing genotype resistance to transient rifampin exposure. Emerg Infect Dis 2014; 20: 1932-1933.
59. Telenti A, Imboden P, Marchesi F, et al. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 1993; 341: 647-650.
60. Jamieson F B, Guthrie J L, Neemuchwala A, Lastovetska O, Melano R G, Mehaffy C. Profiling of rpoB mutations and MICs for rifampin and rifabutin in Mycobacterium tuberculosis. J Clin Microbiol 2014; 52: 2157-2162.
61. Tan Y, Hu Z, Zhao Y, et al. The beginning of the rpoB gene in addition to the rifampin resistance determination region might be needed for identifying rifampin/rifabutin cross-resistance in multidrug-resistant Mycobacterium tuberculosis isolates from Southern China. J Clin Microbiol 2012; 50: 81-85.
62. Ocheretina O, Escuyer V E, Mabou M M, et al. Correlation between genotypic and phenotypic testing for resistance to rifampin in Mycobacterium tuberculosis clinical isolates in Haiti: investigation of cases with discrepant susceptibility results. PLOS ONE 2014; 9: e9056.
63. Andres S, Hillemann D, Rüsch-Gerdes S, Richter E. Occurrence of rpoB mutations in isoniazid-resistant but rifampin-susceptible Mycobacterium tuberculosis isolates from Germany. Antimicrob Agents Chemother 2014; 58: 590-592.
64. Van Deun A, Aung K J, Hossain A, et al. Disputed rpoB mutations can frequently cause important rifampicin resistance among new tuberculosis patients. Int J Tuberc Lung Dis 2015; 19: 185-190.
65. Nakamura M, Harano Y, Koga T. [Isolation of a strain of M. tuberculosis which is considered to be rifampicin-dependent, from a patient with long-lasted smear positive and culture difficult (SPCD) mycobacteria]. Kekkaku 1990; 65: 569-574. [Japanese]
66. Zhong M, Zhang X, Wang Y, et al. An interesting case of rifampicin-dependent/-enhanced multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2010; 14: 40-44.
67. Jin H X, Fu L, Wang S, Zheng M Q, Lu Y. Study on the rifampicin-dependent characteristics of Mycobacterium tuberculosis clincial isolates. Chinese J Antituberculosis 2012; 34: 670-675.
68. Sirgel F A, Warren R M, Bottger E C, Klopper M, Victor T C, van Helden P D. The rationale for using rifabutin in the treatment of MDR and XDR tuberculosis outbreaks. PLOS ONE 2013; 8: e59414.
69. Koch A, Mizrahi V,Warner D F. The impact of drug resistance on Mycobacterium tuberculosis physiology: what can we learn from rifampicin? Emerg Microbes Infect 2014; 3: e17.
70. de Vos M, Muller B, Borrell S, et al. Putative compensatory mutations in the rpoC gene of rifampin-resistant Mycobacterium tuberculosis are associated with ongoing transmission. Antimicrob Agents Chemother 2013; 57: 827 832.
71. Comas I, Borrell S, Roetzer A, et al. Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nat Genet 2012; 44: 106-110.
72. Casali N, Nikolayevskyy V, Balabanova Y, et al. Evolution and transmission of drug-resistant tuberculosis in a Russian population. Nat Genet 2014; 46: 279-286.
73. Takayama K, Kilburn J. Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother 1989; 33: 1493 1499.
74. Telenti A, Philipp W, Sreevatsan S, et al. The emb operon, a unique gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nature Med 1997; 3: 567-570.
75. Ramaswamy S V, Amin A G, Goksel S, et al. Molecular genetic analysis of nucleotide polymorphisms associated with ethambutol resistance in human isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2000; 44: 326 336.
76. Sreevatsan S, Stockbauer K, Pan X, et al. Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 1997; 41: 1677-1681.
77. Safi H, Sayers B, Hazbon M H, Alland D. Transfer of embB codon 306 mutations into clinical Mycobacterium tuberculosis strains alters susceptibility to ethambutol, isoniazid, and rifampin. Antimicrob Agents Chemother 2008; 52: 2027-2034.
78. Alcaide F, Pfyffer G E, Telenti A. Role of embB in natural and acquired resistance to ethambutol in mycobacteria. Antimicrob Agents Chemother 1997; 41: 2270-2273.
79. Safi H, Lingaraju S, Amin A, et al. Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-beta-D-arabinose biosynthetic and utilization pathway genes. Nat Genet 2013; 45: 1190-1197.
80. He L, Wang X, Cui P, et al. ubiA (Rv3806c) encoding DPPR synthase involved in cell wall synthesis is associated with ethambutol resistance in Mycobacterium tuberculosis. Tuberculosis (Edinb) 2015; 95: 149-154.
81. Maruri F, Sterling T R, Kaiga AW, et al. A systematic review of gyrase mutations associated with fluoroquinolone-resistant Mycobacterium tuberculosis and a proposed gyrase numbering system. J Antimicrob Chemother 2012; 67: 819 831.
82. Devasia R, Blackman A, Eden S, et al. High proportion of fluoroquinolone-resistant Mycobacterium tuberculosis isolates with novel gyrase polymorphisms and a gyrA region associated with fluoroquinolone susceptibility. J Clin Microbiol 2012; 50: 1390-1396.
83. Lau RW, Ho P L, Kao RY, et al. Molecular characterization of fluoroquinolone resistance in Mycobacterium tuberculosis: functional analysis of gyrA mutation at position 74. Antimicrob Agents Chemother 2011; 55: 608-614.
84. Perlman D C, El SadrWM, Heifets L B, et al. Susceptibility to levofloxacin of Myocobacterium tuberculosis isolates from patients with HIV-related tuberculosis and characterization of a strain with levofloxacin monoresistance. Community Programs for Clinical Research on AIDS 019 and the AIDS Clinical Trials Group 222 Protocol Team. AIDS 1997; 11: 1473-1478.
85. Von Groll A, Martin A, Jureen P, et al. Fluoroquinolone resistance in Mycobacterium tuberculosis and mutations in gyrA and gyrB. Antimicrob Agents Chemother 2009; 53: 4498-4500.
86. Eilertson B, Maruri F, Blackman A, Herrera M, Samuels D C, Sterling T R. High proportion of heteroresistance in gyrA and gyrB in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 2014; 58: 3270-3275.
87. Zhang Z, Lu J, Wang Y, Pang Y, Zhao Y. Prevalence and molecular characterization of fluoroquinolone-resistant Mycobacterium tuberculosis isolates in China. Antimicrob Agents Chemother 2014; 58: 364-369.
88. Sirgel FA,Warren RM, Streicher EM, Victor T C, van Helden P D, Bottger E C. gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis. J Antimicrob Chemother 2012; 67: 1088-1093.
89. Cui Z,Wang J, Lu J, Huang X, Hu Z. 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.
90. Long Q, Li W, Du Q, et al. gyrA/B fluoroquinolone resistance allele profiles amongst Mycobacterium tuberculosis isolates from mainland China. Int J Antimicrob Agents 2012; 39: 486 489.
91. Nosova E Y, Bukatina A A, Isaeva Y D, Makarova M V, Galkina K Y, Moroz A M. Analysis of mutations in the gyrA and gyrB genes and their association with the resistance of Mycobacterium tuberculosis to levofloxacin, moxifloxacin and gatifloxacin. J Med Microbiol 2013; 62: 108-113.
92. Malik S, Willby M, Sikes D, Tsodikov O V, Posey J E. New insights into fluoroquinolone resistance in Mycobacterium tuberculosis: functional genetic analysis of gyrA and gyrB mutations. PLOS ONE 2012; 7: e39754.
93. Alvarez N, Zapata E, Mejia G I, et al. The structural modeling of the interaction between levofloxacin and the Mycobacterium tuberculosis gyrase catalytic site sheds light on the mechanisms of fluoroquinolones resistant tuberculosis in Colombian clinical isolates. BioMed Res Int 2014; 2014: 367 268.
94. Takiff H, Guerrero E. Current prospects for the fluoroquinolones as first-line tuberculosis therapy. Antimicrob Agents Chemother 2011; 55: 5421-5429.
95. Lu J, Liu M, Wang Y, Pang Y, Zhao Z. Mechanisms of fluoroquinolone monoresistance in Mycobacterium tuberculosis. FEMS Microbiol Lett 2014; 353: 40-48.
96. Louw G E,Warren RM, Gey van PittiusNC, et al. Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux. Am J Respir Crit Care Med 2011; 184: 269-276.
97. Finken M, Kirschner P, Meier A, Wrede A, Bottger E. Molecular basis of streptomycin resistance in Mycobacterium tuberculosis: alterations of the ribosomal protein S12 gene and point mutations within a functional 16S ribosomal RNA pseudoknot. Mol Microbiol 1993; 9: 1239-1246.
98. Nair J, Rouse D A, Bai G H, Morris S L. The rpsL gene and streptomycin resistance in single and multiple drug-resistant strains of Mycobacterium tuberculosis. Mol Microbiol 1993; 10: 521-527.
99. Cooksey R C, Morlock G P, McQueen A, Glickman S E, Crawford J T. Characterization of streptomycin resistance mechanisms among Mycobacterium tuberculosis isolates from patients in New York City. Antimicrob Agents Chemother 1996; 40: 1186-1188.
100. Okamoto S, Tamaru A, Nakajima C, et al. Loss of a conserved 7-methylguanosine modification in 16S rRNA confers lowlevel streptomycin resistance in bacteria. MolMicrobiol 2007; 63: 1096-1106.
101. Reeves A Z, Campbell P J, Sultana R, et al. Aminoglycoside cross-resistance in Mycobacterium tuberculosis due to mutations in the 50 untranslated region of whiB7. Antimicrob Agents Chemother. 2013; 57: 1857-1865.
102. Alangaden G, Kreiswirth B, Aouad A, et al. Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 1998; 42: 1295 1297.
103. Suzuki Y, Katsukawa C, Tamaru A, et al. Detection of kanamycin-resistant Mycobacterium tuberculosis by identifying mutations in the 16S rRNA gene. J Clin Microbiol 1998; 36: 1220-1225.
104. Zaunbrecher M A, Sikes R D, Jr, Metchock B, Shinnick T M, Posey J E. Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2009; 106: 20 004-20 009.
105. Maus C E, Plikaytis B B, Shinnick T M. Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2005; 49: 571 577.
106. Johansen S, Maus C, Plikaytis B, Douthwaite S. Capreomycin binds across the ribosomal subunit interface using tlyAencoded 20-O-methylations in 16S and 23S rRNAs. Mol Cell 2006; 23: 173-182.
107. Maus C E, Plikaytis B B, Shinnick T M.Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2005; 49: 3192-3197.
108. DeBarber A, Mdluli K, Bosman M, Bekker L, Barry C, 3rd. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2000; 97: 9677-9682.
109. Baulard A, Betts J, Engohang-Ndong J, et al. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem 2000; 275: 28 326-28 331.
110. Vannelli T, Dykman A, Ortiz de Montellano P. The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase. J Biol Chem 2002; 277: 12 824-12 829.
111. Strych U, Penland R, Jimenez M, Krause K, Benedik M. Characterization of the alanine racemases from two Mycobacteria. FEMS Microbiol Lett 2001; 196: 93-98.
112. Caceres N, Harris N,Wellehan J, Feng Z, Kapur V, Barletta R. Overexpression of the D-alanine racemase gene confers resistance to D-cycloserine in Mycobacterium smegmatis. J Bacteriol 1997; 179: 5046-5055.
113. Feng Z, Barletta R. Roles of Mycobacterium smegmatis Dalanine: D-alanine ligase and D-alanine racemase in the mechanisms of action of and resistance to the peptidoglycan inhibitor D-cycloserine. Antimicrob Agents Chemother 2003; 47: 283-291.
114. Prosser G A, de Carvalho L P.Metabolomics reveal d-alanine: d-alanine ligase as the target of d-cycloserine in Mycobacterium tuberculosis. ACS Med Chem Lett 2013; 4: 1233-1237.
115. Chen JM, Uplekar S, Gordon S V, Cole S T. A point mutation in cycA partially contributes to the D-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains. PLOS ONE 2012; 7: e43467.
116. Rengarajan J, Sassetti C M, Naroditskaya V, Sloutsky A, Bloom B R, Rubin E J. The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol 2004; 53: 275-282.
117. Ratledge C. Iron, mycobacteria and tuberculosis. Tuberculosis (Edinb) 2004; 84: 110-130.
118. Winder F. Mode of action of the antimycobacterial agents and associated aspects of the molecular biology of mycobacteria. In: Ratledge C, Stanford J, eds. The biology of mycobacteria. New York, NY, USA: Academic Press, 1982: pp 354-438.
119. Zheng J, Rubin E J, Bifani P, et al. para-aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis. J Biol Chem 2013; 288: 23 447-23 456.
120. Chakraborty S, Gruber T, Barry C E, 3rd, Boshoff H I, Rhee K Y. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science 2013; 339: 88-91.
121. Mathys V, Wintjens R, Lefevre P, et al. Molecular genetics of para-aminosalicylic acid resistance in clinical isolates and spontaneous mutants of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2009; 53: 2100-2109.
122. Zhao F, Wang X D, Erber L N, et al. Binding pocket alterations in dihydrofolate synthase confer resistance to paraaminosalicylic acid in clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2014; 58: 1479 1487.
123. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307: 223-227.
124. Koul A, Vranckx L, Dendouga N, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem 2008; 283: 25 273-25 280.
125. Lounis N, Veziris N, Chauffour A, Truffot-Pernot C, Andries K, Jarlier V. Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration. Antimicrob Agents Chemother 2006; 50: 3543-3547.
126. Hartkoorn R C, Uplekar S, Cole S T. Cross-resistance between clofazimine and bedaquiline through upregulation ofMmpL5 in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2014; 58: 2979-2981.
127. Andries K, Villellas C, Coeck N, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLOS ONE 2014; 9: e102135.
128. Stover C K, Warrener P, VanDevanter D R, et al. A smallmolecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000; 405: 962-966.
129. Singh R, Manjunatha U, Boshoff H I, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008; 322: 1392-1395.
130. Manjunatha U H, Boshoff H, Dowd C S, et al. Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006; 103: 431-436.
131. Feuerriegel S, Koser C U, Bau D, et al. Impact of Fgd1 and ddn diversity in Mycobacterium tuberculosis complex on in vitro susceptibility to PA-824. Antimicrob Agents Chemother. 2011; 55: 5718-5722.
132. SaliuO Y, Crismale C, Schwander S K,Wallis R S. Bactericidal activity of OPC-67683 against drug-tolerant Mycobacterium tuberculosis. J Antimicrob Chemother 2007; 60: 994-998.
133. Lee R E, Protopopova M, Crooks E, Slayden R A, Terrot M, Barry C E, 3rd. Combinatorial lead optimization of [1, 2] diamines based on ethambutol as potential antituberculosis preclinical candidates. J Comb Chem 2003; 5: 172-187.
134. Protopopova M, Hanrahan C, Nikonenko B, et al. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial l ibrary of 1, 2 ethylenediamines. J Antimicrob Chemother 2005; 56: 968 974.
135. Tahlan K, Wilson R, Kastrinsky D B, et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2012; 56: 1797-1809.
136. W, Upadhyay A, Fontes F L, et al. Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2014; 58: 6413-6423.
137. Barrett J. Linezolid Pharmacia Corp. Curr Opin Investig Drugs 2000; 1: 181-187.
138. Barbachyn M R, Hutchinson D K, Brickner S J, et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J Med Chem 1996; 39: 680-685.
139. Hillemann D, Rusch-Gerdes S, Richter E. In vitro-selected linezolid-resistant Mycobacterium tuberculosis mutants. Antimicrob Agents Chemother 2008; 52: 800-801.
140. Beckert P, Hillemann D, Kohl TA, et al. rplC T460C identified as a dominant mutation in linezolid-resistant Mycobacterium tuberculosis strains. Antimicrob Agents Chemother 2012; 56: 2743-2745.
141. Zhang Z, Pang Y,Wang Y, Liu C, Zhao Y. Beijing genotype of Mycobacterium tuberculosis is significantly associated with linezolid resistance in multidrug-resistant and extensively drug-resistant tuberculosis in China. Int J Antimicrob Agents 2014; 43: 231-235.
142. Lee M, Lee J, Carroll M W, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 2012; 367: 1508-1518.
143. Yew W W, Lange C. Linezolid in the treatment of drugresistant tuberculosis: the way forward? Int J Tuberc Lung Dis 2014; 18: 631-632.
144. Sun F, Ruan Q, Wang J, et al. Linezolid manifests a rapid and dramatic therapeutic effect for patients with life-threatening tuberculous meningitis. Antimicrob Agents Chemother 2014; 58: 6297-6301.
145. Reddy V M, O'Sullivan J F, Gangadharam P R. Antimycobacterial activities of riminophenazines. J Antimicrob Chemother 1999; 43: 615-623.
146. Cholo M C, Steel H C, Fourie P B, Germishuizen W A, Anderson R. Clofazimine: current status and future prospects. J Antimicrob Chemother 2012; 67: 290-298.
147. Van Deun A, Maug A K, Salim M A, et al. Short, highly effective and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010; 182: 684-692.
148. Piubello A, Harouna S H, Souleymane M B, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis 2014; 18: 1188-1194.
149. Yano T, Kassovska-Bratinova S, Teh J S, et al. Reduction of clofazimine by mycobacterial type 2 NADH: quinone oxidoreductase: a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem 2011; 286: 10 276-10 287.
150. Milano A, Pasca M R, Provvedi R, et al. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5 MmpL5 efflux system. Tuberculosis (Edinb) 2009; 89: 84 90.
151. Zhang S, Chen J, Cui P, Shi W, Zhang W, Zhang Y. Identification of novel mutations associated with clofazimine resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 2015 Jun 4. pii: dkv150. [Epub ahead of print].
152. Farhat M R, Shapiro B J, Kieser K J, et al. Genomic analysis identifies targets of convergent positive selection in drugresistant Mycobacterium tuberculosis. Nat Genet 2013; 45: 1183-1189.
153. Zhang H, Li D, Zhao L, et al. Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance. Nat Genet 2013; 4: 1255-1260.
154. Sun G, Luo T, Yang C, et al. Dynamic population changes in Mycobacterium tuberculosis during acquisition and fixation of drug resistance in patients. J Infect Dis 2012; 20: 1724 1733.
155. Feuerriegel S, Koser C U, Niemann S. Phylogenetic polymorphisms in antibiotic resistance genes of the Mycobacterium tuberculosis complex. J Antimicrob Chemother 2014; 69: 1205-1210.