Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: Classical and new drugs

Journal of Antimicrobial Chemotherapy

Volumn 66, Issue 7, 2011, Pages 1417-1430

  da Silva, Pedro Eduardo Almeida ^a   Palomino, Juan Carlos ^b  

^a FEDERAL UNIVERSITY OF RIO GRANDE   (Brazil)

^b INSTITUTE OF TROPICAL MEDICINE   (Belgium)

Author keywords

Fitness; MDR; Quinolones; TB; XDR

Indexed keywords

1,3 BENZOTHIAZIN 4 ONE; 6,7 DIHYDRO 2 NITRO 6 (4 TRIFLUOROMETHOXYBENZYLOXY) 5H IMIDAZO[2,1 B][1,3]OXAZINE; AMIKACIN; AMINOSALICYLIC ACID; ANTIMALARIAL AGENT; BEDAQUILINE; CAPREOMYCIN; CHLORPROMAZINE; CLARITHROMYCIN; CYCLOSERINE; DELAMANID; ETHAMBUTOL; ETHIONAMIDE; GATIFLOXACIN; ISONIAZID; KANAMYCIN; LINEZOLID; MOXIFLOXACIN; N (2 ADAMANTYL) N' GERANYLETHYLENEDIAMINE; NAS 21; NAS 91; NORFLOXACIN; OFLOXACIN; PYRAZINAMIDE; RIFAMPICIN; STREPTOMYCIN; THIORIDAZINE; TUBERCULOSTATIC AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG; VIOMYCIN;

ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; BACTERIAL TRANSMISSION; BACTERIAL VIRULENCE; DRUG MECHANISM; DRUG TOLERANCE; MINIMUM INHIBITORY CONCENTRATION; MISSENSE MUTATION; MOLECULAR MECHANICS; MULTIDRUG RESISTANCE; MYCOBACTERIUM SMEGMATIS; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; NONSENSE MUTATION; REVIEW; TUBERCULOSIS;

ANTITUBERCULAR AGENTS; DRUG RESISTANCE, BACTERIAL; GENES, BACTERIAL; HUMANS; METABOLIC NETWORKS AND PATHWAYS; MYCOBACTERIUM TUBERCULOSIS;

EID: 79958784137     PISSN: 03057453     EISSN: 14602091     Source Type: Journal    
DOI: 10.1093/jac/dkr173     Document Type: Review

References (177)

1. Almeida da Silva PE, Ainsa J. Drugs and drug interactions. In: Palomino JC, Leão S, Ritacco V, eds. Tuberculosis 2007: From Basic Science to Patient Care. pp. 635-60. http://www.tuberculosistextbook.com/tb/drugs.htm (30 January 2011, date last accessed).
2. Wolinsky E, Reginster A, Steenken W Jr. Drug-resistant tubercle bacilli in patients under treatment with streptomycin. Am Rev Tuberc 1948; 58: 335-43.
3. WHO. Anti-Tuberculosis Drug Resistance in the World. Fourth Global Report. 2008. WHO/HTM/TB/2008.394.
4. Dye C. Doomsday postponed? Preventing and reversing epidemics of drug-resistant tuberculosis. Nat Rev Microbiol 2009; 7: 81-7.
5. Cole ST, Brosch R, Parkhill J et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393: 537-44.
6. Camus JC, Pryor MJ, Médigue C et al. Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Microbiology 2002; 148: 2967-73.
7. Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 1998; 79: 3-29.
8. WHO. Multidrug and Extensively Drug-Resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response. 2010. WHO/HTM/TB/2010.3. http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf (4 April 2011, date last accessed).
9. Musser JM. Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev 1995; 8: 496-514.
10. Jarlier V, Nikaido H. Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 1994; 123: 11-8.
11. De Rossi E, Aínsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol Rev 2006; 30: 36-52.
12. Stephan J, Mailaender C, Etienne G et al. Multidrug resistance of a porin deletion mutant of Mycobacterium smegmatis. Antimicrob Agents Chemother 2004; 48: 4163-70.
13. Danilchanka O, Pavlenok M, Niederweis M. Role of porins for uptake of antibiotics by Mycobacterium smegmatis. Antimicrob Agents Chemother 2008; 52: 3127-34.
14. Flores AR, Parsons LM, Pavelka MS Jr. Genetic analysis of the b-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to b-lactam antibiotics. Microbiology 2005; 151: 521-32.
15. Siroy A, Mailaender C, Harder D et al. Rv1698 of Mycobacterium tuberculosis represents a new class of channel-forming outer membrane proteins. J Biol Chem 2008; 283: 17827-37.
16. Song H, Sandie R, Wang Y et al. Identification of outer membrane proteins of Mycobacterium tuberculosis. Tuberculosis (Edinb) 2008; 88: 526-44.
17. Nguyen L, Pieters J. Mycobacterial subversion of chemotherapeutic reagents and host defense tactics: challenges in tuberculosis drug development. Annu Rev Pharmacol Toxicol 2008; 49: 427-53.
18. Morris RP, Nguyen L, Gatfield J et al. Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2005; 102: 12200-5.
19. Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic-a vision for applied use. Biochem Pharmacol 2006; 71: 910-8.
20. Nguyen L, Thompson CJ. Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm. Trends Microbiol 2006; 14: 304-12.
21. Kochi A, Vareldzis B, Styblo K. Multidrug-resistant tuberculosis and its control. Res Microbiol 1993; 144: 104-10.
22. Safi H, Sayers B, Hazbón MH et al. Transfer of embB codon 306 mutations into clinical Mycobacterium tuberculosis strains alters susceptibility to ethambutol, isoniazid, and rifampin. Antimicrob Agents Chemother 2008; 52: 2027-34.
23. Gillespie SH. Tuberculosis: evolution in millennia and minutes. Biochem Soc Trans 2007; 35: 1317-20.
24. Middlebrook G, Cohn ML. Some observations on the pathogenicity of isoniazid-resistant variants of tubercle bacilli. Science 1953; 118: 297-9.
25. Middlebrook G. Isoniazid-resistance and catalase activity of tubercle bacilli; a preliminary report. Am Rev Tuberc 1954; 69: 471-2.
26. Zhang Y, Heym B, Allen B et al. The catalase/peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 1992; 358: 591-3.
27. Rawat R, Whitty A, Tonge PJ. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc Natl Acad Sci USA 2003; 100: 13881-6.
28. Silva MS, Senna SG, Ribeiro MO et al. Mutations in katG, inhA, and ahpC genes of Brazilian isoniazid-resistant isolates of Mycobacterium tuberculosis. J Clin Microbiol 2003; 41: 4471-4.
29. Ramaswamy SV, Reich R, Dou SJ et al. Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 1241-50.
30. Hazbón MH, 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: 2640-9.
31. Larsen MH, Vilchèze C, Kremer L et al. Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol Microbiol 2002; 46: 453-66.
32. Vilchèze C, Jacobs WR Jr. The mechanism of isoniazid killing: clarity through the scope of genetics. Annu Rev Microbiol 2007; 61: 35-50.
33. van Doorn HR, de Haas PE, Kremer K et al. Public health impact of isoniazid-resistant Mycobacterium tuberculosis strains with a mutation at amino-acid position 315 of katG: a decade of experience in The Netherlands. Clin Microbiol Infect 2006; 12: 769-75.
34. van Soolingen D, de Haas PE, van Doorn HR et al. Mutations at amino acid position 315 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance, and successful transmission of Mycobacterium tuberculosis in the Netherlands. J Infect Dis 2000; 182: 1788-90.
35. Banerjee A, Dubnau E, Quemard A et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 1994; 263: 227-30.
36. Leung ET, Ho PL, Yuen KY et al. Molecular characterization of isoniazid resistance in Mycobacterium tuberculosis: identification of a novel mutation in inhA. Antimicrob Agents Chemother 2006; 50: 1075-8.
37. Rinder H, Thomschke A, Rüsch-Gerdes S et al. Significance of ahpC promoter mutations for the prediction of isoniazid resistance in Mycobacterium tuberculosis. Eur J Clin Microbiol Infect Dis 1998; 17: 508-11.
38. Sherman DR, Mdluli K, Hickey MJ et al. Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 1996; 272: 1641-3.
39. Miesel L, Weisbrod TR, Marcinkeviciene JA et al. NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis. J Bacteriol 1998; 180: 2459-67.
40. Cardoso RF, Cardoso MA, Leite CQ et al. Characterization of ndh gene of isoniazid resistant and susceptible Mycobacterium tuberculosis isolates from Brazil. Mem Inst Oswaldo Cruz 2007; 102: 59-61.
41. Sim E, Pinter K, Mushtaq A et al. Arylamine N-acetyltransferases: from structure to function. Drug Metab Rev 2008; 40: 479-510.
42. Sim E, Pinter K, Mushtaq A et al. Arylamine N-acetyltransferases: a pharmacogenomic approach to drug metabolism and endogenous function. Biochem Soc Trans 2003; 31: 615-9.
43. Payton M, Auty R, Delgoda R et al. Cloning and characterization of arylamine N-acetyltransferase genes from Mycobacterium smegmatis and Mycobacterium tuberculosis: increased expression results in isoniazid resistance. J Bacteriol 1999; 181: 1343-7.
44. Sim E, Sandy J, Evangelopoulos D et al. Arylamine N-acetyltransferases in mycobacteria. Curr Drug Metab 2008; 9: 510-9.
45. Bhakta S, Besra GS, Upton AM et al. Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target. J Exp Med 2004; 199: 1191-9.
46. Ando H, Kitao T, Miyoshi-Akiyama T et al. Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis. Mol Microbiol 2011; 9: 1615-28.
47. Dalla Costa ER, Ribeiro MO, Silva MS et al. Correlations of mutations in katG, oxyR-ahpC and inhA genes and in vitro susceptibility in Mycobacterium tuberculosis clinical strains segregated by spoligotype families from tuberculosis prevalent countries in South America. BMC Microbiol 2009; 9: 39.
48. Fu LM, Shinnick TM. Understanding the action of INH on a highly INH-resistant Mycobacterium tuberculosis strain using Genechips. Tuberculosis (Edinb) 2007; 87: 63-70.
49. Colangeli R, Helb D, Sridharan S et al. 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: 1829-40.
50. Wilson M, DeRisi J, Kristensen HH et al. Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. Proc Natl Acad Sci USA 1999; 96: 12833-8.
51. Rattan A, Kalia A, Ahmad N. Multidrug-resistant Mycobacterium tuberculosis: molecular perspectives. Emerg Infect Dis 1998; 4: 195-209.
52. Blanchard JS. Molecular mechanisms of drug resistance in Mycobacterium tuberculosis. Annu Rev Biochem 1996; 65: 215-39.
53. Mitchison DA. Basic mechanisms of chemotherapy. Chest 1979; 76 Suppl 6: 771-81.
54. Telenti A, Imboden P, Marchesi F et al. Direct, automated detection of rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 1993; 37: 2054-8.
55. Somoskovi A, Parsons LM, Salfinger M. The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium tuberculosis. Respir Res 2001; 2: 164-8.
56. Caws M, Duy PM, Tho DQ et al. Mutations prevalent among rifampinand isoniazid-resistant Mycobacterium tuberculosis isolates from a hospital in Vietnam. J Clin Microbiol 2006; 44: 2333-7.
57. Heep M, Rieger U, Beck D et al. Mutations in the beginning of the rpoB gene can induce resistance to rifamycins in both Helicobacter pylori and Mycobacterium tuberculosis. Antimicrob Agents Chemother 2000; 44: 1075-7.
58. Wang Q, Yue J, Zhang L et al. A newly identified 191A/C mutation in the Rv2629 gene that was significantly associated with rifampin resistance in Mycobacterium tuberculosis. J Proteome Res 2007; 6: 4564-71.
59. Chakravorty S, Aladegbami B, Motiwala AS et al. Rifampin resistance, Beijing-W clade-single nucleotide polymorphism cluster group 2 phylogeny, and the Rv2629 191-C allele in Mycobacterium tuberculosis strains. J Clin Microbiol 2008; 46: 2555-60.
60. Yang B, Koga H, Ohno H et al. Relationship between antimycobacterial activities of rifampicin, rifabutin and KRM-1648 and rpoB mutations of Mycobacterium tuberculosis. J Antimicrob Chemother 1998; 42: 621-8.
61. Cavusoglu C, Karaca-Derici Y, Bilgic A. In-vitro activity of rifabutin against rifampicin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations. Clin Microbiol Infect 2004; 10: 662-5.
62. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001; 164: 7-12.
63. Traore H, Fissette K, Bastian I et al. Detection of rifampicin resistance in Mycobacterium tuberculosis isolates from diverse countries by a commercial line probe assay as an initial indicator of multidrug resistance. Int J Tuberc Lung Dis 2000; 4: 481-4.
64. Mitchison DA. The action of antituberculosis drugs in short-course chemotherapy. Tubercle 1985; 66: 219-25.
65. Konno K, Feldmann FM, McDermott W. Pyrazinamide susceptibility and amidase activity of tubercle bacilli. Am Rev Respir Dis 1967; 95: 461-9.
66. 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: 662-7.
67. Zhang Y, Wade MM, Scorpio A et al. Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother 2003; 52: 790-5.
68. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis 2003; 7: 6-21.
69. Zimhony O, Vilchèze C, Arai M et al. Pyrazinoic acid and its n-propyl ester inhibit fatty acid synthase type I in replicating tubercle bacilli. Antimicrob Agents Chemother 2007; 51: 752-4.
70. Scorpio A, Lindholm-Levy P, Heifets L et al. Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 1997; 41: 540-3.
71. Juréen P, Werngren J, Toro JC et al. Pyrazinamide resistance and pncA gene mutations in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2008; 52: 1852-4.
72. Cheng SJ, Thibert L, Sanchez T et al. 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: 528-32.
73. Sreevatsan S, Pan X, Zhang Y et al. Mutations associated with pyrazinamide resistance in pncA of Mycobacterium tuberculosis complex organisms. Antimicrob Agents Chemother 1997; 41: 636-40.
74. Sun Z, Zhang Y. Reduced pyrazinamidase activity and the natural resistance of Mycobacterium kansasii to the antituberculosis drug pyrazinamide. Antimicrob Agents Chemother 1999; 43: 537-42.
75. Moazed D, Noller HF. Interaction of antibiotics with functional sites in 16S ribosomal RNA. Nature 1987; 327: 389-94.
76. Crofton J, Mitchison DA. Streptomycin resistance in pulmonary tuberculosis. Br Med J 1948; 2: 1009-15.
77. Ramón-García S, Otal I, Martín C et al. Novel streptomycin resistance gene from Mycobacterium fortuitum. Antimicrob Agents Chemother 2006; 50: 3920-2.
78. Gillespie SH. Evolution of drug resistance in Mycobacterium tuberculosis: clinical and molecular perspective. Antimicrob Agents Chemother 2002; 46: 267-74.
79. Zhang Y, Telenti A. Genetics of drug resistance in Mycobacterium tuberculosis. In: Hatfull GF, Jacobs WR, eds. Molecular Genetics Mycobacteria. Washington, DC: American Society for Microbiology Press, 2000; 235-56.
80. Silva PE, Bigi F, Santangelo MP et al. Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob Agents Chemother 2001; 45: 800-4.
81. Okamoto S, Tamaru A, Nakajima C et al. Loss of a conserved 7-methylguanosine modification in 16S rRNA confers low-level streptomycin resistance in bacteria. Mol Microbiol 2007; 63: 1096-106.
82. Spies FS, da Silva PE, Ribeiro MO et al. Identification of mutations related to streptomycin resistance in clinical isolates of Mycobacterium tuberculosis and possible involvement of efflux mechanism. Antimicrob Agents Chemother 2008; 52: 2947-9.
83. Takayama K, Armstrong EL, Kunugi KA et al. Inhibition by ethambutol of mycolic acid transfer into the cell wall of Mycobacterium smegmatis. Antimicrob Agents Chemother 1979; 16: 240-2.
84. Telenti A, Philipp WJ, Sreevatsan S et al. The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med 1997; 3: 567-70.
85. Sreevatsan S, Stockbauer KE, Pan X et al. Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 1997; 41: 1677-81.
86. Lee AS, Othman SN, Ho YM et al. Novel mutations within the embB gene in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2004; 48: 4447-9.
87. Ahmad S, Jaber AA, Mokaddas E. Frequency of embB codon 306 mutations in ethambutol-susceptible and -resistant clinical Mycobacterium tuberculosis isolates in Kuwait. Tuberculosis (Edinb) 2007; 87: 123-9.
88. Hazbón MH, Bobadilla del Valle M, Guerrero MI et al. Role of embB codon 306 mutations in Mycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than ethambutol resistance. Antimicrob Agents Chemother 2005; 49: 3794-802.
89. Plinke C, Cox HS, Kalon S et al. Tuberculosis ethambutol resistance: concordance between phenotypic and genotypic test results. Tuberculosis (Edin) 2009; 89: 448-52.
90. Laszlo A, Rahman M, Espinal M et al. Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reference Laboratory Network: five rounds of proficiency testing, 1994-1998. Int J Tuberc Lung Dis 2002; 6: 748-56.
91. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009; 13: 1320-30.
92. Goss WA, Deitz WH, Cook TM. Mechanism of action of nalidixic acid on Escherichia coli. II. Inhibition of deoxyribonucleic acid synthesis. J Bacteriol 1965; 89: 1068-74.
93. Alvirez-Freites EJ, Carter JL, Cynamon MH. In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 2002; 46: 1022-5.
94. Nuermberger EL, Yoshimatsu T, Tyagi S et al. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med 2004; 170: 1131-4.
95. Rustomjee R, Diacon AH, Allen J et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother 2008; 52: 2831-5.
96. Aubry A, Pan XS, Fisher LM et al. Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity. Antimicrob Agents Chemother 2004; 48: 1281-8.
97. Wang JC. DNA topoisomerases. Annu Rev Biochem 1996; 65: 635-92.
98. Drlica K. Mechanism of fluoroquinolone action. Curr Opin Microbiol 1999; 2: 504-8.
99. Takiff HE, Salazar L, Guerrero C et al. Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 1994; 38: 773-80.
100. Cheng AF, Yew WW, Chan EW et al. Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 2004; 48: 596-601.
101. Sun Z, Zhang J, Zhang X et al. Comparison of gyrA gene mutations between laboratory-selected ofloxacin-resistant Mycobacterium tuberculosis strains and clinical isolates. Int J Antimicrob Agents 2008; 31: 115-21.
102. Aubry A, Veziris N, Cambau E et al. Novel gyrase mutations in quinolone-resistant and -hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother 2006; 50: 104-12.
103. von Groll A, Martin A, Juréen P et al. Fluoroquinolone resistance in Mycobacterium tuberculosis and mutations in gyrA and gyrB. Antimicrob Agents Chemother 2009; 53: 4498-500.
104. Somasundaram S, Paramasivan NC. Susceptibility of Mycobacterium tuberculosis strains to gatifloxacin and moxifloxacin by different methods. Chemotherapy 2006; 52: 190-5.
105. Aeschlimann JR. The role of multidrug efflux pumps in the antibiotic resistance of Pseudomonas aeruginosa and other Gram-negative bacteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2003; 23: 916-24.
106. Escribano I, Rodríguez JC, Llorca B et al. Importance of the efflux pump systems in the resistance of Mycobacterium tuberculosis to fluoroquinolones and linezolid. Chemotherapy 2007; 53: 397-401.
107. Choudhuri BS, Bhakta S, Barik R et al. 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: 279-85.
108. Pasca MR, Guglierame P, Arcesi F et al. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2004; 48: 3175-8.
109. Braibant M, Gilot P, Content J. The ATP binding cassette (ABC) transport systems of Mycobacterium tuberculosis. FEMS Microbiol Rev 2000; 24: 449-67.
110. Hegde SS, Vetting MW, Roderick S et al. A fluoroquinolone resistance protein from Mycobacterium tuberculosis that mimics DNA. Science 2005; 308: 1480-3.
111. Tsukamura M, Mizuno S. Cross-resistant relationships among the aminoglucoside antibiotics in Mycobacterium tuberculosis. J Gen Microbiol 1975; 88: 269-74.
112. Alangaden GJ, Kreiswirth BN, Aouad A et al. Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 1998; 42: 1295-7.
113. Maus CE, Plikaytis BB, Shinnick TM. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2005; 49: 3192-7.
114. Jugheli L, Bzekalava N, de Rijk P et al. High level of cross-resistance between kanamycin, amikacin, and capreomycin among Mycobacterium tuberculosis isolates from Georgia and a close relation with mutations in the rrs gene. Antimicrob Agents Chemother 2009; 53: 5064-8.
115. McClatchy JK, Kanes W, Davidson PT et al. Cross-resistance in M. tuberculosis to kanamycin, capreomycin and viomycin. Tubercle 1977; 58: 29-34.
116. Johansen SK, Maus CE, Plikaytis BB et al. Capreomycin binds across the ribosomal subunit interface using tlyA-encoded 2′-O-methylations in 16S and 23S rRNAs. Mol Cell 2006; 23: 173-82.
117. Sander P, Meier A, Bottger EC. Ribosomal drug resistance in mycobacteria. Res Microbiol 1996; 147: 59-67.
118. Krüüner A, Juréen P, Levina K et al. Discordant resistance to kanamycin and amikacin in drug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 2971-3.
119. Zaunbrecher MA, Sikes RD Jr, Metchock B et al. Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2009; 106: 20004-9.
120. Engström A, Perskvist N, Werngren J et al. Comparison of clinical isolates and in vitro selected mutants reveals that tlyA is not a sensitive genetic marker for capreomycin resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 2011; 66: 1247-54.
121. Campbell PJ, Morlock GP, Sikes RD et al. Molecular detection of mutations associated with first and second-line drug resistance compared with conventional drug susceptibility testing in M. tuberculosis. Antimicrob Agents Chemother 2011; Epub ahead of print 7 February 2011.
122. Wang F, Langley R, Gulten G et al. Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 2007; 204: 73-8.
123. Vilchèze C, Wang F, Arai M et al. Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. Nat Med 2006; 12: 1027-9.
124. Vilchèze C, Weisbrod TR, Chen B et al. Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. Antimicrob Agents Chemother 2005; 49: 708-20.
125. Vilchèze C, Av-Gay Y, Attarian R et al. Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis. Mol Microbiol 2008; 69: 1316-29.
126. Lehmann J. para-Aminosalicylic acid in the treatment of tuberculosis. Lancet 1946; i: 15-6.
127. Rengarajan J, Sassetti CM, Naroditskaya V et al. The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol 2004; 53: 275-82.
128. 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: 2100-9.
129. Leung KL, Yip CW, Yeung YL et al. Usefulness of resistant gene markers for predicting treatment outcome on second-line anti-tuberculosis drugs. J Appl Microbiol 2010; 109: 2087-94.
130. Feuerriegel S, Koser C, Trube L et al. Thr202Ala in thyA is a marker for the Latin American Mediterranean lineage of the Mycobacterium tuberculosis complex rather than para-aminosalicylic acid resistance. Antimicrob Agents Chemother 2010; 54: 4794-8.
131. Andini N, Nash KA. Intrinsic macrolide resistance of the Mycobacterium tuberculosis complex is inducible. Antimicrob Agents Chemother 2006; 50: 2560-2.
132. Bosne-David S, Barros V, Verde SC et al. Intrinsic resistance of Mycobacterium tuberculosis to clarithromycin is effectively reversed by subinhibitory concentrations of cell wall inhibitors. J Antimicrob Chemother 2000; 46: 391-5.
133. Bhusal Y, Shiohira CM, Yamane N. Determination of in vitro synergy when three antimicrobial agents are combined against Mycobacterium tuberculosis. Int J Antimicrob Agents 2005; 26: 292-7.
134. Stoffels K, Traore H, Vanderbist F et al. The effect of combined tobramycin-clarithromycin on Mycobacterium tuberculosis isolates. Int J Tuberc Lung Dis 2009; 13: 1041-4.
135. Zhang Y. The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol 2005; 45: 529-64.
136. Alcala L, Ruiz-Serrano M, Turegano C et al. In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs. Antimicrob Agents Chemother 2003; 47: 416-7.
137. Cynamon M, Klemens S, Sharpe C et al. Activities of several oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother 1999; 43: 1189-91.
138. Alffenaar JW, van der Laan T, Simons S et al. Susceptibility of clinical Mycobacterium tuberculosis isolates to a potentially less toxic derivate of linezolid, PNU-100480. Antimicrob Agents Chemother 2011; 55: 1287-9.
139. Richter E, Rüsch-Gerdes S, Hillemann D. First linezolid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2007; 51: 1534-6.
140. Hillemann D, Rüsch-Gerdes S, Richter E. In vitro-selected linezolid-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2008; 52: 800-1.
141. Sander P, Belova L, Kidan YG et al. Ribosomal and non-ribosomal resistance to oxazolidinones: species-specific idiosyncrasy of ribosomal alterations. Mol Microbiol 2002; 46: 1295-304.
142. Cáceres NE, Harris NB, Wellehan JF et al. Overexpression of the d-alanine racemase gene confers resistance to d-cycloserine in Mycobacterium smegmatis. J Bacteriol 1997; 179: 5046-55.
143. Stover CK, Warrener P, VanDevanter DR et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000; 405: 962-6.
144. Rivers EC, Mancera RL. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discov Today 2008; 13: 1090-8.
145. Ginsberg AM, Laurenzi MW, Rouse DJ et al. Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects. Antimicrob Agents Chemother 2009; 53: 3720-5.
146. Singh R, Manjunatha U, Boshoff HI et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008; 322: 1392-5.
147. Manjunatha UH, Boshoff H, Dowd CS et al. Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006; 103: 431-6.
148. Matsumoto M, Hashizume H, Tomishige T et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 2006; 3: e466.
149. Protopopova M, Hanrahan C, Nikonenko B et al. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother 2005; 56: 968-74.
150. Jia L, Coward L, Gorman GS et al. Pharmacoproteomic effects of isoniazid, ethambutol, and N-geranyl-N′-(2-adamantyl)ethane-1,2-diamine (SQ109) on Mycobacterium tuberculosis H37Rv. J Pharmacol Exp Ther 2005; 315: 905-11.
151. Andries K, Verhasselt P, Guillemont J et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307: 223-7.
152. Diacon AH, Pym A, Grobusch M et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009; 360: 2397-405.
153. Koul A, Dendouga N, Vergauwen K et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol 2007; 3: 323-4.
154. Petrella S, Cambau E, Chauffour A et al. Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. Antimicrob Agents Chemother 2006; 50: 2853-6.
155. Cole ST, Alzari PM. Microbiology. TB-a new target, a new drug. Science 2005; 307: 214-5.
156. Huitric E, Verhasselt P, Koul A et al. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother 2010; 54: 1022-8.
157. Gratraud P, Surolia N, Besra GS et al. Antimycobacterial activity and mechanism of action of NAS-91. Antimicrob Agents Chemother 2008; 52: 1162-6.
158. Bhowruth V, Brown AK, Besra GS. Synthesis and biological evaluation of NAS-21 and NAS-91 analogues as potential inhibitors of the mycobacterial FAS-II dehydratase enzyme Rv0636. Microbiology 2008; 154: 1866-75.
159. Ordway D, Viveiros M, Leandro C et al. Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 917-22.
160. Martins M, Dastidar SG, Fanning S et al. Potential role of non-antibiotics (helper compounds) in the treatment of multidrug-resistant Gram-negative infections: mechanisms for their direct and indirect activities. Int J Antimicrob Agents 2008; 31: 198-208.
161. Dutta NK, Mehra S, Kaushal D. A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine. PLoS One 2010; 5: e10069.
162. Makarov V, Manina G, Mikusova K et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 2009; 324: 801-4.
163. Pasca MR, Degiacomi G, Ribeiro AL et al. Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob Agents Chemother 2010; 54: 1616-8.
164. Manina G, Bellinzoni M, Pasca MR et al. Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance. Mol Microbiol 2010; 77: 1172-85.
165. Andersson DI. The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol 2006; 9: 461-5.
166. O'Sullivan DM, McHugh TD, Gillespie SH. Analysis of rpoB and pncA mutations in the published literature: an insight into the role of oxidative stress in Mycobacterium tuberculosis evolution? J Antimicrob Chemother 2005; 55: 674-9.
167. Billington OJ, McHugh TD, Gillespie SH. Physiological cost of rifampin resistance induced in vitro in Mycobacterium tuberculosis. Antimicrob Agents Chemother 1999; 43: 1866-9.
168. Gagneux S, Long CD, Small PM et al. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 2006; 312: 1944-6.
169. Gagneux S. Fitness cost of drug resistance in Mycobacterium tuberculosis. Clin Microbiol Infect 2009; 15 Suppl 1: 66-8.
170. Gagneux S, Burgos MV, DeRiemer K et al. Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis. PLoS Pathog 2006; 2: e61.
171. Sander P, Springer B, Prammananan T et al. Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob Agents Chemother 2002; 46: 1204-11.
172. Böttger EC, Springer B, Pletschette M et al. Fitness of antibioticresistant microorganisms and compensatory mutations. Nat Med 1998; 4: 1343-4.
173. Motiwala AS, Dai Y, Jones-Lopez EC et al. Mutations in extensively drug-resistant Mycobacterium tuberculosis that do not code for known drug-resistance mechanisms. J Infect Dis 2010; 201: 881-8.
174. vonGroll A, Martin A, Felix Cet al. Fitness studyof the RDRio lineage and Latin American-Mediterranean family of Mycobacterium tuberculosis in the city of Rio Grande, Brazil. FEMS Immunol Med Microbiol 2010; 58: 119-27.
175. Cohen T, Murray M. Modelling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nat Med 2004; 10: 1117-21.
176. Wright A, Zignol M, Van Deun A et al. Epidemiology of antituberculosis drug resistance 2002-07: an updated analysis of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Lancet 2009; 373: 1861-73.
177. TB Drug Resistance Mutation Database. http://www.tbdreamdb.com/index.html (30 March 2011, date last accessed).