Skip to main content

Advertisement

SpringerLink
Log in

Mycobacterium tuberculosis mutants with multidrug resistance: History of origin, genetic and molecular mechanisms of resistance, and emerging challenges

  • Theoretical Articles and Reviews
  • Published:
Russian Journal of Genetics Aims and scope Submit manuscript

Abstract

The review summarizes the data on the Mycobacterium tuberculosis mutations that lead to multidrug resistance (MDR) to various antibiotics. MDR strains arose over the past 30 years as a variety of antituberculosis drugs were introduced in medicine, and they largely discount the results of chemotherapy for tuberculosis. The most dangerous of them are strains with extensive drug resistance (XDR), which are resistant to four or five different drugs on average. The molecular mechanisms that make a strain resistant are considered. XDR and MDR strains result from successive and usually independent resistance mutations, which arise in various regions of the mycobacterial genome. In addition, the formation of resistant strains is affected by the phenomenon of tolerance and mycobacterial latency in infected tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Corbett, E.L., Watt, C.J., Walker, N., et al., The Growing Burden of Tuberculosis: Global Trends and Interactions with the HIV Epidemic, Arch. Int. Med., 2003, vol. 163, no. 9, pp. 1009–1021.

    Article  Google Scholar 

  2. Brosch, R., Gordon, S.V., Marmiesse, M., et al., A New Evolutionary Scenario for the Mycobacterium tuberculosis Complex, Proc. Natl. Acad. Sci. USA, 2002, vol. 99, no. 6, pp. 3684–3689.

    Article  PubMed  CAS  Google Scholar 

  3. Arnold, C., Molecular Evolution of Mycobacterium tuberculosis, Clin. Microbiol. Infect., 2007, vol. 13, no. 2, pp. 120–128.

    Article  PubMed  CAS  Google Scholar 

  4. Gutierrez, M.C., Brisse, S., Brosch, R., et al., Ancient Origin and Gene Mosaicism of the Progenitor of Mycobacterium tuberculosis, PLoS Pathog., 2005, vol. 1, no. 1, p. 5.

    Article  CAS  Google Scholar 

  5. Shenoi, S. and Friedland, G., Extensively Drug-Resistant Tuberculosis: A New Face to an Old Pathogen, Annu. Rev. Med., 2009, vol. 60, pp. 307–320.

    Article  PubMed  CAS  Google Scholar 

  6. Victor, T.C., van Helden, P.D., and Warren, R., Prediction of Drug Resistance in Mycobacterium tuberculosis: Molecular Mechanisms, Tools, and Applications, IUBMB Life, 2002, vol. 53, nos. 4–5, pp. 231–237.

    Article  PubMed  CAS  Google Scholar 

  7. Beck-Sague, C., Dooley, S.W., Hutton, M.D., et al., Hospital Outbreak of Multidrug-Resistant Mycobacterium tuberculosis Infections: Factors in Transmission to Staff and HIV-Infected Patients, JAMA, 1992, vol. 268, no. 10, pp. 1280–1286.

    Article  PubMed  CAS  Google Scholar 

  8. Edlin, B.R., Tokars, J.I., Grieco, M.H., et al., An Outbreak of Multidrug-Resistant Tuberculosis among Hospitalized Patients with the Acquired Immunodeficiency Syndrome, New Eng. J. Med., 1992, vol. 326, no. 23, pp. 1514–1521.

    Article  PubMed  CAS  Google Scholar 

  9. Plikaytis, B.B., Marden, J.L., Crawford, J.T., et al., Multiplex PCR Assay Specific for the Multidrug-Resistant Strain W of Mycobacterium tuberculosis, J. Clin. Microbiol., 1994, vol. 32, no. 6, pp. 1542–1546.

    PubMed  CAS  Google Scholar 

  10. Pym, A., Cole, S., Mechanisms of Drug Resistance in Mycobacterium tuberculosis, Bacterial Resistance to Antimicrobials, Wax, R., Taber, H., Salyers, A., and Lewis, K., Eds., CRC Press, 2008, pp. 313–342.

  11. Sotgiu, G., Ferrara, G., Matteelli, A., et al., Epidemiology and Clinical Management of XDR-TB: A Systematic Review by TBNET, Eur. Respir. J., 2009, vol. 33, no. 4, pp. 871–881.

    Article  PubMed  CAS  Google Scholar 

  12. Toungoussova, O.S., Nizovtseva, N., Mariandyshev, A., et al., Impact of Drug-Resistant Mycobacterium tuberculosis on Treatment Outcome of Culture-Positive Cases of Tuberculosis in the Archangel Oblast, Russia, in 1999, Eur. J. Clin. Microbiol. Infect. Dis., 2004, vol. 23, no. 3, pp. 174–179.

    Article  PubMed  CAS  Google Scholar 

  13. Cox, H.S., Orozco, J.D., Male, R., et al., Multidrug-Resistant Tuberculosis in Central Asia, Emerg. Infect. Dis., 2004, vol. 10, no. 5, pp. 865–872.

    PubMed  Google Scholar 

  14. Ellner, J.J., The Emergence of Extensively Drug-Resistant Tuberculosis: A Global Health Crisis Requiring New Interventions: I. The Origins and Nature of the Problem, Clin. Transl. Sci., 2008, vol. 1, no. 3, pp. 249–254.

    Article  PubMed  CAS  Google Scholar 

  15. Zignol, M., Hosseini, M.S., Wright, A., et al., Global Incidence of Multidrug-Resistant Tuberculosis, J. Infect. Dis., 2006, vol. 194, no. 4, pp. 479–485.

    Article  PubMed  Google Scholar 

  16. Multidrug and Extensively Drug-Resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response, Genewa: World Health Organization, 2010.

  17. Vasil’ev, A.V., Current Tuberculosis Problems in the North-West of Russia, Problemy Tuberkuleza, 1999, no. 3, pp. 5–7.

  18. Chiang, C.Y., Centis, R., and Migliori, G.B., Drug-Resistant Tuberculosis: Past, Present, Future, Respirology, 2010, vol. 15, no. 3, pp. 413–432.

    Article  PubMed  Google Scholar 

  19. Erokhin, V., Overview and MDR-TB Research Activities, in Recent Opportunities in TB Drug Discovery and Diagnostics, (Proc. Joint NIAID-ISTC Workshop), Moscow, 2010, p. 21.

  20. Comas, I. and Gagneux, S., The Past and Future of Tuberculosis Research, PLoS Pathog., 2009, vol. 5, no. 10, pp. 1–7.

    Article  CAS  Google Scholar 

  21. Leimane, V., Riekstina, V., Holtz, T.H., et al., Clinical Outcome of Individualised Treatment of Multidrug-Resistant Tuberculosis in Latvia: A Retrospective Cohort Study, Lancet, 2005, vol. 365, no. 9456, pp. 318–326.

    PubMed  Google Scholar 

  22. Nathanson, E., Lambregts-van Weezenbeek, C., Rich, M.L., et al., Multidrug-Resistant Tuberculosis Management in Resource-Limited Settings, Emerg. Infect. Dis., 2006, vol. 12, no. 9, pp. 1389–1397.

    Article  PubMed  Google Scholar 

  23. Holtz, T.H. and Cegielski, J.P., Origin of the Term XDR-TB, Eur. Respir. J., 2007, vol. 30, no. 2, p. 396.

    Article  PubMed  CAS  Google Scholar 

  24. Gandhi, N.R., Moll, A., Sturm, A.W., et al., Extensively Drug-Resistant Tuberculosis as a Cause of Death in Patients Co-Infected with Tuberculosis and HIV in a Rural Area of South Africa, Lancet, 2006, vol. 368, no. 9547, pp. 1575–1580.

    Article  PubMed  Google Scholar 

  25. Koenig, R., Drug-Resistant Tuberculosis in South Africa, XDR TB and HIV Prove a Deadly Combination, Science, 2008, vol. 319, no. 5865, pp. 894–897.

    Article  Google Scholar 

  26. Shah, N.S., Wright, A., Bai, G.H., et al., Worldwide Emergence of Extensively Drug-Resistant Tuberculosis, Emerg. Infect. Dis., 2007, vol. 13, no. 3, pp. 380–387.

    Article  PubMed  CAS  Google Scholar 

  27. Kim, D.H., Kim, H.J., Park, S.K., et al., Treatment Outcomes and Long-Term Survival in Patients with Extensively Drug-Resistant Tuberculosis, Am. J. Respir. Crit. Care Med., 2008, vol. 178, no. 10, pp. 1075–1082.

    Article  PubMed  CAS  Google Scholar 

  28. Migliori, G.B., Lange, C., Centis, R., et al., Resistance to Second-Line Injectables and Treatment Outcomes in MDR and XDR Tuberculosis Cases, Eur. Respir. J., 2008, vol. 31, no. 6, pp. 1155–1159.

    Article  PubMed  CAS  Google Scholar 

  29. Keshavjee, S., Gelmanova, I.Y., Farmer, P.E., et al., Treatment of Extensively Drug-Resistant Tuberculosis in Tomsk, Russia: A Retrospective Cohort Study, Lancet, 2008, vol. 372, no. 9647, pp. 1403–1409.

    Article  PubMed  Google Scholar 

  30. Jain, A. and Mondal, R., Extensively Drug-Resistant Tuberculosis: Current Challenges and Threats, FEMS Immunol. Med. Microbiol., 2008, vol. 53, no. 2, pp. 145–150.

    Article  PubMed  CAS  Google Scholar 

  31. Dye, C., Doomsday Postponed? Preventing and Reversing Epidemics of Drug-Resistant Tuberculosis, Nat. Rev. Microbiol., 2009, vol. 7, no. 1, pp. 81–87.

    Article  PubMed  CAS  Google Scholar 

  32. Hugonnet, J.E., Tremblay, L.W., Boshoff, H.I., et al., Meropenem-Clavulanate Is Effective against Extensively Drug-Resistant Mycobacterium tuberculosis, Science, 2009, vol. 323, no. 5918, pp. 1215–1218.

    Article  PubMed  CAS  Google Scholar 

  33. Wright, G.D., The Antibiotic Resistome: The Nexus of Chemical and Genetic Diversity, Nat. Rev. Microbiol., 2007, vol. 5, no. 3, pp. 175–186.

    Article  PubMed  CAS  Google Scholar 

  34. Jarlier, V. and Nikaido, H., Mycobacterial Cell Walls: Structure and Role in Natural Resistance to Antibiotics, FEMS Microbiol. Lett., 1994, vol. 123, nos. 1–2, pp. 11–18.

    Article  PubMed  CAS  Google Scholar 

  35. De Rossi, E., Ansa, J.A., and Riccardi, G., Role of Mycobacterial Efflux Transporters in Drug Resistance: An Unresolved Question, FEMS Microbiol. Rev.,, vol. 30, no. 1, pp. 36–52.

  36. D’Costa, V.M., McGrann, K.M., Hughes, D.W., and Wright, G.D., Sampling the Antibiotic Resistome, Science, 2006, vol. 311, no. 5759, pp. 374–377.

    Article  PubMed  Google Scholar 

  37. MacLean, R.C., Hall, A.R., Perron, G.G., and Buckling, A., The Population Genetics of Antibiotic Resistance: Integrating Molecular Mechanisms and Treatment Contexts, Nat. Rev. Genet., 2010, vol. 11, no. 6, pp. 405–414.

    Article  PubMed  CAS  Google Scholar 

  38. Nikaido, H. and Normark, S., Sensitivity of Escherichia coli to Various Beta-Lactams Is Determined by the Interplay of Outer Membrane Permeability and Degradation by Periplasmic Beta-Lactamases: A Quantitative Predictive Treatment, Mol. Microbiol., 1987, vol. 1, no. 1, pp. 29–36.

    Article  PubMed  CAS  Google Scholar 

  39. Parrish, N.M., Dick, J.D., and Bishai, W.R., Mechanisms of Latency in Mycobacterium tuberculosis, Trends Microbiol., 1998, vol. 6, no. 3, pp. 107–112.

    Article  PubMed  CAS  Google Scholar 

  40. Shleeva, M.O., Salina, E.G., and Kaprel’yants, A.S., Latent Form of the Tubercle Bacillus, Mikrobiologiya, 2010, vol. 79, no. 1, pp. 3–15.

    CAS  Google Scholar 

  41. Prozorov, A.A. and Danilenko, V.N., “Toxin-Antitoxin” Systems in Bacterium: An Apoptosis Instrument or a Metabolism Regulator?, Mikrobiologiya, 2010, vol. 79, no. 2, pp. 147–159.

    Google Scholar 

  42. Prozorov, A.A. and Danilenko, V.N., Mycobacteria of the Tuberculosis Complex: Genomics, Molecular Epidemiology, and Evolution Paths, Usp. Sovrem. Biol., 2011, vol. 130, no. 3, pp. 210–221.

    Google Scholar 

  43. Canetti, G.J., Changes in Tuberculosis as Seen by a Pathologist, Am. Rev. Tuberc., 1959, vol. 79, no. 5, pp. 684–686.

    PubMed  CAS  Google Scholar 

  44. Zhang, Y. and Yew, W.W., Mechanisms of Drug Resistance in Mycobacterium tuberculosis, Int. J. Tuberc. Lung. Dis., 2009, vol. 13, no. 11, pp. 1320–1330.

    PubMed  CAS  Google Scholar 

  45. Sandgren, A., Strong, M., Muthukrishnan, P., et al., Tuberculosis Drug Resistance Mutation Database, PLoS Med., 2009, vol. 6, no. 2, pp. 0132–0136.

    Article  CAS  Google Scholar 

  46. Musser, J.M., Antimicrobial Agent Resistance in Mycobacteria: Molecular Genetic Insights, Clin. Microbiol. Rev., 1995, no. 4, pp. 496–514.

  47. Drobniewski, F.A. and Wilson, S.M., The Rapid Diagnosis and Rifampicin Resistance in Mycobacterium tuberculosis a Molecular Story, J. Med. Microbiol., 1998, vol. 47, no. 3, pp. 189–196.

    Article  PubMed  CAS  Google Scholar 

  48. Mani, C., Selvakumar, N., Narayanan, S., and Narayanan, P.R., Mutations in the rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates from India, J. Clin. Microbiol., 2001, vol. 39, no. 8, pp. 2987–2990.

    Article  PubMed  CAS  Google Scholar 

  49. Hazbon, M.H. and 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, vol. 50, no. 8, pp. 2640–2649.

    Article  PubMed  CAS  Google Scholar 

  50. Bakonyte, D., Baranauskaite, A., Cicenaite, J., et al., Molecular Characterization of Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates in Lithuania, Antimicrob. Agents Chemother., 2003, vol. 47, no. 6, pp. 2009–2011.

    Article  PubMed  CAS  Google Scholar 

  51. Ng, V.H., Cox, J.S., Sousa, A.O., et al., Role of KatG Catalase-Peroxidase in Mycobacterial Pathogenesis: Countering the Phagocyte Oxidative Burst, Mol. Microbiol., 2004, vol. 52, no. 5, pp. 1291–1302.

    Article  PubMed  CAS  Google Scholar 

  52. Sherman, D.R., Mdluli, K., Hickey, M.J., et al., Compensatory ahpC Gene Expression in Isoniazid Resistant Mycobacterium tuberculosis, Science, 1996, vol. 272, no. 5268, pp. 1641–1643.

    Article  PubMed  CAS  Google Scholar 

  53. Saint-Joanis, B., Souchon, H., Wilming, M., et al., Use of Site-Directed Mutagenesis to Probe the Structure, Function and Isoniazid Activation on the Catalase/Peroxidase, KatG, from M. tuberculosis, Biochem. J., 1999, vol. 338, no. 3, pp. 753–760.

    Article  PubMed  CAS  Google Scholar 

  54. Pym, A.S., Domenech, P., Honor, N., et al., Regulation of Catalase-Peroxidase (KatG) Expression, Isoniazid Sensitivity and Virulence by furA of Mycobacterium tuberculosis, Mol. Microbiol., 2001, vol. 40, no. 4, pp. 879–889.

    Article  PubMed  CAS  Google Scholar 

  55. Telenti, A., Philipp, W.J., Sreevatsan, S., et al., The emb Operon, a Gene Cluster of Mycobacterium tuberculosis Involved in Resistance to Ethambutol, Nat. Med., 1997, vol. 3, no. 5, pp. 567–570.

    Article  PubMed  CAS  Google Scholar 

  56. Hazbon, M.H., Bobadilla del Valle, M., Guerrero, M.I., 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, vol. 49, no. 9, pp. 3794–3802.

    Article  PubMed  CAS  Google Scholar 

  57. Safi, H., Sayers, B., Hazbon, M.H., et al., Transfer of embB 306 Mutations into Clinical Mycobacterium tuberculosis Alters Susceptibility to Ethambutol, Isoniazid and Rifampin, Antimicrob. Agents Chemother., 2008, vol. 52, no. 6, pp. 2027–2034.

    Article  PubMed  CAS  Google Scholar 

  58. Zhang, Y. and Mitchison, D., The Curious Characteristics of Pyrazinamide: A Review, Int. J. Tuberc. Lung Dis., 2003, vol. 7, no. 1, pp. 6–21.

    PubMed  CAS  Google Scholar 

  59. Zhang, Y., Scorpio, A., Nikaido, H., and Sun, Z., Role of Acid pH and Deficient Efflux of Pyrazinoic Acid in the Unique Susceptibility of Mycobacterium tuberculosis to Pyrazinamide, J. Bacteriol., 1999, vol. 181, no. 7, pp. 2044–2049.

    PubMed  CAS  Google Scholar 

  60. Scorpio, A. and Zhang, Y., Mutations in pncA, a Gene Encoding Pyrazinamidase/Nicotinamidase, Cause Resistance to the Antituberculous Drug Pyrazinamide in the Tubercle Bacillus, Nat. Med., 1996, vol. 2, no. 6, pp. 662–667.

    Article  PubMed  CAS  Google Scholar 

  61. Honor, N. and Cole, S.T., Streptomycin Resistance in Mycobacteria, Antimicrob. Agents Chemother., 1994, vol. 38, no. 2, pp. 238–242.

    Google Scholar 

  62. Finken, M., Kirschner, P., Meier, A., et al., Molecular Basis of Streptomycin-Resistance in Mycobacterium tuberculosis: Alteration of the Ribosomal Protein S12 Gene and Point Mutations within a Functional 16S rRNA Pseudoknot, Mol. Microbiol., 1993, vol. 9, no. 6, pp. 1239–1246.

    Article  PubMed  CAS  Google Scholar 

  63. Honor, N., Marchal, G., and Cole, S.T., Novel Mutation in 16S rRNA Associated with Streptomycin Dependence in Mycobacterium tuberculosis, Antimicrob. Agents Chemother., 1995, vol. 39, no. 3, pp. 769–770.

    Google Scholar 

  64. 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, vol. 63, no. 4, pp. 1096–1106.

    Article  PubMed  CAS  Google Scholar 

  65. Spies, F.S., Silva, P.E., Ribeiro, M.O., 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, vol. 52, no. 8, pp. 2947–2949.

    Article  PubMed  CAS  Google Scholar 

  66. Alangaden, G., Kreiswirth, B., Aouad, A., et al., Mechanism of Resistance to Amikacin and Kanamycin in Mycobacterium tuberculosis, Antimicrob. Agents Chemother., vol. 42, no. 5, pp. 1295–1297.

  67. 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, vol. 36, no. 5, pp. 1220–1225.

    PubMed  CAS  Google Scholar 

  68. Maus, C.E., Plikaytis, B.B., and Shinnick, T.M., Mutation of tlyA Confers Capreomycin Resistance in Mycobacterium tuberculosis, Antimicrob. Agents Chemother., 2005, vol. 49, no. 2, pp. 571–577.

    Article  PubMed  CAS  Google Scholar 

  69. Johansen, S.K., Maus, C.E., Plikaytis, B.B., and Douthwaite, S., Capreomycin Binds across the Ribosomal Subunit Interface Using tlyA-Encoded 2′-O-Methylations in 16S and 23S rRNAs, Mol. Cell,, vol. 23, no. 2, pp. 173–182.

  70. Maus, C.E., Plikaytis, B.B., and Shinnick, T.M., Molecular Analysis of Cross-Resistance to Capreomycin, Kanamycin, Amikacin, and Viomycin in Mycobacterium tuberculosis, Antimicrob. Agents Chemother., 2005, vol. 49, no. 8, pp. 3192–3197.

    Article  PubMed  CAS  Google Scholar 

  71. Cheng, A.F., Yew, W.W., Chan, E.W., et al., Multiplex PCR Amplimer Conformation Analysis for Rapid Detection of gyrA Mutations in Fluoroquinolone-Resistant Mycobacterium tuberculosis Clinical Isolates, Antimicrob. Agents Chemother., 2004, vol. 48, no. 2, pp. 596–601.

    Article  PubMed  CAS  Google Scholar 

  72. Chang, K.C., Yew, W.W., and Chan, R.C., Rapid Assays for Fluoroquinolone Resistance in Mycobacterium tuberculosis: A Systematic Review and Meta-Analysis, J. Antimicrob. Chemother., 2010, vol. 65, no. 8, pp. 1551–1561.

    Article  PubMed  CAS  Google Scholar 

  73. Takiff, H.E., 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, vol. 38, no. 4, pp. 773–780.

    PubMed  CAS  Google Scholar 

  74. Zhou, J., Dong, Y., Zhao, X., et al., Selection of Antibiotic Resistance: Allelic Diversity among Fluoroquinolone-Resistant Mutations, J. Infect. Dis., 2000, vol. 182, no. 2, pp. 517–525.

    Article  PubMed  CAS  Google Scholar 

  75. Kocagz, T., Hackbarth, C.J., Unsal, I., et al., Gyrase Mutations in Laboratory-Selected, Fluoroquinolone-Resistant Mutants of Mycobacterium tuberculosis H37Ra, Antimicrob. Agents Chemother., 1996, vol. 40, no. 8, pp. 1768–1774.

    Google Scholar 

  76. Alangaden, G.J., Manavathu, E.K., Vakulenko, S.B., et al., Characterization of Fluoroquinolone-Resistant Mutant Strains of Mycobacterium tuberculosis Selected in the Laboratory and Isolated from Patients, Antimicrob. Agents Chemother., 1995, vol. 39, no. 8, pp. 1700–1703.

    PubMed  CAS  Google Scholar 

  77. Pasca, M.R., Guglierame, P., Arcesi, F., et al., Rv2686c-Rv2687c-Rv2688c, an ABC Fluoroquinolone Efflux Pump in Mycobacterium tuberculosis, Antimicrob. Agents Chemother., 2004, vol. 48, no. 8, pp. 3175–3178.

    Article  PubMed  CAS  Google Scholar 

  78. Hegde, S.S., Vetting, M.W., Roderick, S.L., et al., A Fluoroquinolone Resistance Protein from Mycobacterium tuberculosis That Mimics DNA, Science, 2005, vol. 308, no. 5727, pp. 1480–1483.

    Article  PubMed  CAS  Google Scholar 

  79. DeBarber, A.E., Mdluli, K., Bosman, M., et al., Ethionamide Activation and Sensitivity in Multidrug-Resistant Mycobacterium tuberculosis, Proc. Natl. Acad. Sci. USA, 2000, vol. 97, no. 17, pp. 9677–9682.

    Article  PubMed  CAS  Google Scholar 

  80. Baulard, A.R., Betts, J.C., Engohang-Ndong, J., et al., Activation of the Pro-Drug Ethionamide Is Regulated in Mycobacteria, J. Biol. Chem., 2000, vol. 275, no. 36, pp. 28326–28331.

    PubMed  CAS  Google Scholar 

  81. Vannelli, T.A. and Dykman, A., and Ortiz de Montellano, P.R., The Antituberculosis Drug Ethionamide Is Activated by a Flavoprotein Monooxygenase, J. Biol. Chem., 2002, vol. 277, no. 15, pp. 12824–12829.

    Article  PubMed  CAS  Google Scholar 

  82. Banerjee, A., Dubnau, E., Qumard, A., et al., InhA, a Gene Encoding a Target for Isoniazid and Ethionamide in Mycobacterium tuberculosis, Science, 1994, vol. 263, no. 5144, pp. 227–230.

    Article  PubMed  CAS  Google Scholar 

  83. Ramon-Garcia, S., Martin, C., Thompson, C.J., and Ainsa, J.A., The Role of the Mycobacterium tuberculosis P55 Efflux Pump in Intrinsic Drug Resistance, Oxidative Stress Responses and Growth, Antimicrob. Agents Chemother., 2009, vol. 53, no. 9, pp. 3675–3682.

    Article  PubMed  CAS  Google Scholar 

  84. Morris, R.P., Nguyen, L., Gatfield, J., et al., Ancestral Antibiotic Resistance in Mycobacterium tuberculosis, Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 34, pp. 12200–12205.

    Article  PubMed  CAS  Google Scholar 

  85. Nguyen, L. and Thompson, C.J., Foundations of Antibiotic Resistance in Bacterial Physiology-the Mycobacterial Paradigm, Trends Microbiol., 2006, vol. 14, no. 7, pp. 304–312.

    Article  PubMed  CAS  Google Scholar 

  86. Bekker, O.B., Elizarov, S.M., Alekseeva, M.G., et al., Ca2+-Dependent Modulation of Antibiotic Resistance in Streptomyces lividans 66 and Streptomyces coelicolor A3(2), Mikrobiologiya, 2008, vol. 77, no. 5, pp. 630–638.

    CAS  Google Scholar 

  87. Wallis, R.S., Patil, S., Cheon, S.H., et al., Drug Tolerance in Mycobacterium tuberculosis, Antimicrob. Agents Chemother., 1999, vol. 43, no. 11, pp. 2600–2606.

    PubMed  CAS  Google Scholar 

  88. Alland, D., Steyn, A.J., Weisbrod, T., et al., Characterization of a Mycobacterium tuberculosis iniBAC Promoter, a Promoter That Responds to Cell Wall Biosynthesis Inhibition, J. Bacteriol., 2000, vol. 182, no. 7, pp. 1802–1811.

    Article  PubMed  CAS  Google Scholar 

  89. Colangeli, R., Helb, D., Sridharan, S., et al., Transcriptional Regulation of Multi-Drug Tolerance and Antibiotic-Induced Responses by the Histone-Like Protein Lsr2 in M. tuberculosis, Mol. Microbiol., 2005, vol. 55, no. 6, pp. 1829–1840.

    Article  PubMed  CAS  Google Scholar 

  90. Colangeli, R., Helb, D., Vilcheze, C., et al., The Mycobacterium tuberculosis iniA Gene Is Essential for Activity of an Efflux Pump That Confers Drug Tolerance to Both Isoniazid and Ethambutol, PLoS Pathog., 2007, vol. 3, no. 6, pp. 0780–0792.

    Article  CAS  Google Scholar 

  91. Siddiqi, N., Das, R., Pathak, N., et al., Mycobacterium tuberculosis Isolate with a Distinct Genomic Identity Overexpresses a Tap-Like Efflux Pump, Infection, 2004, vol. 32, no. 2, pp. 109–111.

    Article  PubMed  CAS  Google Scholar 

  92. Boshoff, H.I., Myers, T.G., Copp, B.R., et al., The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism: Novel Insights in Drug Mechanisms of Action, J. Biol. Chem., 2004, vol. 279, no. 8, pp. 40174–40184.

    Article  PubMed  CAS  Google Scholar 

  93. Pandey, D.P. and Gerdes, K., Toxin-Antitoxin Loci Are Highly Abundant in Free-Living but Lost from Host-Associated Prokaryotes, Nucleic Acids Res., 2005, vol. 33, no. 3, pp. 966–976.

    Article  PubMed  CAS  Google Scholar 

  94. Van Melderen, L., Saavedra, De., and Bast, M., Bacterial Toxin-Antitoxin Systems: More Than Selfish Entities?, PLoS Genet., 2009, vol. 5, no. 3, pp. 1–6.

    Google Scholar 

  95. Buts, L., Lah, J., Dao-Thi, M., et al., Toxin-Antitoxin Modules as Bacterial Metabolic Stress Managers, Trends Biochem. Sci., 2005, vol. 30, no. 12, pp. 672–679.

    Article  PubMed  CAS  Google Scholar 

  96. Ramage, H.R., Connolly, L.E., and Cox, J., Comprehensive Functional Analysis of Mycobacterium tuberculosis Toxin-Antitoxin Systems: Implications for Pathogenesis, Stress Responses, and Evoluties, PLoS Genet., 2009, vol. 5, no. 12, pp. 1–14.

    Article  CAS  Google Scholar 

  97. Korch, S.B., Contreras, H., and Clark-Curtiss, J.E., Three Mycobacterium tuberculosis Rel Toxin-Antitoxin Modules Inhibit Mycobacterial Growth and Are Expressed in Infected Human Macrophages, J. Bacteriol., 2009, vol. 191, no. 5, pp. 1618–1630.

    Article  PubMed  CAS  Google Scholar 

  98. Huang, F. and He, Z.G., Characterization of an Interplay between a Mycobacterium tuberculosis MazF Homolog, Rv1495 and Its Sole DNA Topoisomerase, Nucleic Acids Res., 2010, vol. 38, no. 22, pp. 8219–8230.

    Article  PubMed  CAS  Google Scholar 

  99. Yang, M., Gao, C., Wang, Y., et al., Characterization of the Interaction and Cross-Regulation of Three Mycobacterium tuberculosis RelBE Modules, PLoS One, 2010, vol. 5, no. 5, pp. 1–12.

    CAS  Google Scholar 

  100. Miallau, L., Faller, M., Chiang, J., et al., Structure and Proposed Activity of a Member of the VapBC Family of Toxin-Antitoxin Systems VapBC-5 from Mycobacterium tuberculosis, J. Biol. Chem., 2009, vol. 284, no. 1, pp. 276–283.

    Article  PubMed  CAS  Google Scholar 

  101. Ellner, J.J., The Emergence of Extensively Drug-Resistant Tuberculosis: A Global Health Crisis Requiring New Interventions: II. Scientific Advances That May Provide Solutions, Clin. Transl. Sci., 2009, vol. 2, no. 1, pp. 80–84.

    Article  PubMed  CAS  Google Scholar 

  102. Werngren, J. and Hoffner, S.E., Deciphering an Outbreak of Drug-Resistant Mycobacterium tuberculosis, J. Clin. Microbiol., 2003, vol. 41, no. 4, pp. 1520–1524.

    Article  PubMed  CAS  Google Scholar 

  103. The New Profile of Drug-Resistant Tuberculosis in Russia: A Global and Local Perspective, (Summary Joint Workshop), Washington, DC: Natl. Acad. Press, 2011.

  104. Koul, A., Arnoult, E., Lounis, N., et al., The Challenge of New Drug Discovery for Tuberculosis, Nature, 2011, vol. 469, no. 7331, pp. 483–490.

    Article  PubMed  CAS  Google Scholar 

  105. Ma, Z., Lienhardt, C., McIlleron, H., et al., Global Tuberculosis Drug Development Pipeline: The Need and the Reality, Lancet, 2010, vol. 375, no. 9731, pp. 2100–2109.

    Article  PubMed  Google Scholar 

  106. Tomioka, H., Prospects for the Development of New Antituberculous Drugs Putting Our Hopes on New Drug Targets, Kekkaku, 2010, vol. 85, no. 11, pp. 815–822.

    PubMed  Google Scholar 

  107. Shi, R. and Sugawara, I., Development of New Anti-Tuberculosis Drug Candidates, Tohoku J. Exp. Med., 2010, vol. 221, no. 2, pp. 97–106.

    Article  PubMed  CAS  Google Scholar 

  108. Danilenko, V.N., Osolodkin, D.I., Lakatosh, S.A., et al., Bacterial Eukaryotic Type Serine-Threonine Protein Kinases: Tools for Targeted Anti-Infective Drug Design, Curr. Top. Med. Chem., 2011, vol. 11, no. 11. pp. 1352–1369.

    Article  PubMed  CAS  Google Scholar 

  109. Kurosu, M. and Begari, E., Bacterial Protein Kinase Inhibitors, Molecules, 2010, vol. 15, no. 3, pp. 1531–1553.

    Article  PubMed  CAS  Google Scholar 

  110. Miller, J.R., Dunham, S., Mochalkin, I., et al., A Class of Selective Antibacterials Derived from a Protein Kinase Inhibitor Pharmacophore, Proc. Natl. Acad. Sci. USA, 2009, vol. 106, no. 6, pp. 1737–1742.

    Article  PubMed  CAS  Google Scholar 

  111. Prozorov, A.A. and Danilenko, V.N., Allolysis Phenomenon in Bacteria, Mikrobiologiya, 2011, vol. 80, no. 1, pp. 1–9.

    CAS  Google Scholar 

  112. Bekker, O.B., Mavletova, D.A., Lyubimova, I.K., et al., Secondary Lysis Induction of Cultures of Streptomyces lividans by Inhibitors of Eukaryotic Type Serine-Threonine Protein Kinases, Mikrobiologiya, 2012 (in press).

  113. Ishmetova, R.I., Rusinov, G.L., Kravchenko, M.A., et al., Antituberculous and Radioprotector Activity of Some 2,5-Substituted Tetrazoles, Pharm. Chem. J., 2000, vol. 34, no. 8, pp. 23–24.

    Article  Google Scholar 

  114. Rusinov, G.L., Latosh, N.I., Ishmetova, R.I., et al., Synthesis and Tuberculostatic Activity of Some Substituted Amino Acid Methyl Esters with Sym-Tetrazine Moietie, Pharm. Chem. J., 2005, vol. 39, no. 1, pp. 10–12.

    Article  CAS  Google Scholar 

  115. Ginsberg, A.M., Laurenzi, M.W., Rouse, D.J., et al., Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects, Antimicrob. Agents Chemother., 2009, vol. 53, no. 9, pp. 3720–3725.

    Article  PubMed  CAS  Google Scholar 

  116. 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, vol. 3, pp. 2131–2144.

    Article  CAS  Google Scholar 

  117. Arjon, A. and Castaner, R., TMC-207 (R-207910) Is a Novel Diarylquinoline with a Unique Biological Target: The F0 Subunit of Mycobacterial ATP Synthase, Drugs Fut., 2008, vol. 33, no. 12, p. 1018.

    Article  Google Scholar 

  118. Jia, L., Tomaszewski, J.E., Hanrahan, C., et al., Pharmacodynamics and Pharmacokinetics of SQ109, a New Diamine-Based Antitubercular Drug, Br. J. Pharmacol., 2009, vol. 144, pp. 80–87.

    Article  CAS  Google Scholar 

  119. Arora, S., Eradication of Mycobacterium tuberculosis Infection in 2 Months with LL-3858: A Preclinical Study, Int. J. Tuberc. Lung Dis., 2004, vol. 8, p. 29.

    Google Scholar 

  120. Alcala, L., Ruiz-Serrano, M.J., Perez-Fernandez, 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, vol. 47, no. 1, pp. 416–417.

    Article  PubMed  CAS  Google Scholar 

  121. Makarov, V., Manina, G., Mikusova, K., et al., Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis, Science, 2009, vol. 324, no. 5928, pp. 801–804.

    Article  PubMed  CAS  Google Scholar 

  122. Charushin, V.N., Tolshchina, S.G., Rusinov, G.L., et al. Russian Inventor’s Certificate no. 2007551348, 2011 (unpublished).

Download references

Author information

Authors and Affiliations

  1. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia

    A. A. Prozorov, M. V. Zaichikova & V. N. Danilenko

Authors
  1. A. A. Prozorov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. V. Zaichikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. N. Danilenko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. A. Prozorov.

Additional information

Original Russian Text © A.A. Prozorov, M.V. Zaichikova, V.N. Danilenko, 2012, published in Genetika, 2012, Vol. 48, No. 1, pp. 5–20.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prozorov, A.A., Zaichikova, M.V. & Danilenko, V.N. Mycobacterium tuberculosis mutants with multidrug resistance: History of origin, genetic and molecular mechanisms of resistance, and emerging challenges. Russ J Genet 48, 1–14 (2012). https://doi.org/10.1134/S1022795411120118

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1022795411120118

Keywords

Search

Navigation