1887

Abstract

Drug-resistant tuberculosis poses a significant problem for treatment. The mechanisms of resistance to the front-line drug isoniazid (INH) are complex and can be mediated by , and other unknown genes. To identify the percentage of INH-resistant strains with no or mutation, this study characterized a panel of 28 clinical isolates of and five mutants derived from H37Rv resistant to INH. Seventeen of 33 resistant strains (51 %) had mutations with 12 of the 17 strains having the most common KatG Ser315Thr mutation. Three of the 17 strains with the KatG 315 mutation had an additional mutation in the promoter and were resistant to a high level of INH. Seventeen of the 33 INH-resistant strains (51 %) had mutations. The most common promoter mutation was −15C→T and was present in 13 of the 17 mutations. This promoter mutation occurred alone without mutations and was associated with a low level of INH and ethionamide resistance. However, other mutations were associated with mutations. No mutations were found in the gene. Three of 33 strains (9 %) had no mutations in , or , indicating that their resistance was due to a new mechanism of resistance. Detection of the KatG Ser315Thr mutation and the −15C→T mutation accounted for 76 % (25/33) of the INH-resistant strains and should be useful for rapid detection of INH-resistant strains by molecular tests.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.46718-0
2006-11-01
2019-10-22
Loading full text...

Full text loading...

/deliver/fulltext/jmm/55/11/1527.html?itemId=/content/journal/jmm/10.1099/jmm.0.46718-0&mimeType=html&fmt=ahah

References

  1. Baker, L. V., Brown, T. J., Maxwell, O., Gibson, A. L., Fang, Z., Yates, M. D. & Drobniewski, F. A. ( 2005; ). Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates from England and Wales reveals the phylogenetic significance of the ahpC −46A polymorphism. Antimicrob Agents Chemother 49, 1455–1464.[CrossRef]
    [Google Scholar]
  2. Bakonyte, D., Baranauskaite, A., Cicenaite, J., Sosnovskaja, A. & Stakenas, P. ( 2003; ). Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical isolates in Lithuania. Antimicrob Agents Chemother 47, 2009–2011.[CrossRef]
    [Google Scholar]
  3. Banerjee, A., Dubnau, E., Quemard, A., Balasubramanian, V., Um, K. S., Wilson, T., Collins, D., de Lisle, G. & Jacobs, W. R., Jr ( 1994; ). inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263, 227–230.[CrossRef]
    [Google Scholar]
  4. Baulard, A. R., Betts, J. C., Engohang-Ndong, J., Quan, S., McAdams, R. A., Brennan, P. J., Locht, C. & Besra, G. S. ( 2000; ). Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem 275, 28326–28331.
    [Google Scholar]
  5. Broussy, S., Coppel, Y., Nguyen, M., Bernadou, J. & Meunier, B. ( 2003; ). 1H and 13C NMR characterization of hemiamidal isoniazid-NAD(H) adducts as possible inhibitors of InhA reductase of Mycobacterium tuberculosis. Chemistry 9, 2034–2038.[CrossRef]
    [Google Scholar]
  6. Cole, S. T., Brosch, R., Parkhill, J. & 39 other authors ( 1998; ). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544.[CrossRef]
    [Google Scholar]
  7. DeBarber, A. E., Mdluli, K., Bosman, M., Bekker, L. G. & Barry, C. E., III ( 2000; ). Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 97, 9677–9682.[CrossRef]
    [Google Scholar]
  8. Heym, B., Alzari, P. M., Honore, N. & Cole, S. T. ( 1995; ). Missense mutations in the catalase-peroxidase gene, katG, are associated with isoniazid resistance in Mycobacterium tuberculosis. Mol Microbiol 15, 235–245.[CrossRef]
    [Google Scholar]
  9. Lee, A. S. G., Lim, I. H. K., Tang, L. L. H., Telenti, A. & Wong, S. Y. ( 1999; ). Contribution of kasA analysis to detection of isoniazid-resistant Mycobacterium tuberculosis in Singapore. Antimicrob Agents Chemother 43, 2087–2089.
    [Google Scholar]
  10. Lee, A. S. G., Teo, A. S. M. & Wong, S.-Y. ( 2001; ). Novel mutations in ndh in isoniazid-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 45, 2157–2159.[CrossRef]
    [Google Scholar]
  11. Madison, B. M., Siddiqi, S. H., Heifets, L., Gross, W., Higgins, M., Warren, N., Thompson, A., Morlock, G. & Ridderhof, J. C. ( 2004; ). Identification of a Mycobacterium tuberculosis strain with stable, low-level resistance to isoniazid. J Clin Microbiol 42, 1294–1295.[CrossRef]
    [Google Scholar]
  12. Mdluli, K., Slayden, R. A., Zhu, Y., Ramaswamy, S., Pan, X., Mead, D., Crane, D. D., Musser, J. M. & Barry, C. E. ( 1998; ). Inhibition of a Mycobacterium tuberculosis β-ketoacyl ACP synthase by isoniazid. Science 280, 1607–1610.[CrossRef]
    [Google Scholar]
  13. Middlebrook, G. ( 1954; ). Isoniazid resistance and catalase activity of tubercle bacilli: a preliminary report. Am Rev Tuberc 69, 471–472.
    [Google Scholar]
  14. Miesel, L., Weisbrod, T. R., Marcinkeviciene, J. A., Bittman, R. & Jacobs, W. R, Jr ( 1998; ). NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis. J Bacteriol 180, 2459–2467.
    [Google Scholar]
  15. Morlock, G. P., Metchock, B., Sikes, D., Crawford, J. T. & Cooksey, R. C. ( 2003; ). ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 47, 3799–3805.[CrossRef]
    [Google Scholar]
  16. Musser, J. M., Kapur, V., Williams, D. L., Kreiswirth, B. N., van Soolingen, D. & van Embden, J. D. ( 1996; ). Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance. J Infect Dis 173, 196–202.[CrossRef]
    [Google Scholar]
  17. Ramaswamy, S. V., Reich, R., Dou, S.-J., Jasperse, L., Pan, X., Wanger, A., Quitugua, T. & Graviss, E. A. ( 2003; ). Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 47, 1241–1250.[CrossRef]
    [Google Scholar]
  18. Raviglione, M. C. ( 2003; ). The TB epidemic from 1992 to 2002. Tuberculosis 83, 4–14.[CrossRef]
    [Google Scholar]
  19. Rozwarski, D. A., Grant, G. A., Barton, D. H. R., Jacobs, W. R., Jr & Sacchettini, J. C. ( 1998; ). Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279, 98–102.[CrossRef]
    [Google Scholar]
  20. Sajduda, A., Brzostek, A., Poplawska, M., Augustynowicz-Kopec, E., Zwolska, Z., Niemann, S., Dziadek, J. & Hillemann, D. ( 2004; ). Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland. J Clin Microbiol 42, 2425–2431.[CrossRef]
    [Google Scholar]
  21. Sherman, D. R., Mdluli, K., Hickey, M. J., Arain, T. M., Morris, S. L., Barry, C. E., III & Stover, C. K. ( 1996; ). Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272, 1641–1643.[CrossRef]
    [Google Scholar]
  22. Shoeb, H. A., Bowman, B. U., Jr, Ottolenghi, A. C. & Merola, A. J. ( 1985; ). Evidence for the generation of active oxygen by isoniazid treatment of extracts of Mycobacterium tuberculosis H37Ra. Antimicrob Agents Chemother 27, 404–407.[CrossRef]
    [Google Scholar]
  23. Siddiqi, S. H. ( 1992; ). Antimicrobial susceptibility testing: radiometric (BACTEC) tests for slowly growing mycobacteria. In Clinical Microbiology Procedures Handbook, pp.14–25. Edited by H. D. Isenberg. Washington, DC: American Society for Microbiology.
  24. Telenti, A., Honoré, N., Bernasconi, C., March, J., Ortega, A., Heym, B., Takiff, H. E. & Cole, S. T. ( 1997; ). Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: a blind study at reference laboratory level. J Clin Microbiol 35, 719–723.
    [Google Scholar]
  25. Vilchèze, C., Weisbrod, T. R., Chen, B., Kremer, L., Hazbón, M. H., Wang, F., Alland, D., Sacchettini, J. C. & Jacobs, W. R., Jr ( 2005; ). Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. Antimicrob Agents Chemother 49, 708–720.[CrossRef]
    [Google Scholar]
  26. Wengenack, N. L., Todorovic, S., Yu, L. & Rusnak, F. ( 1998; ). Evidence for differential binding of isoniazid by Mycobacterium tuberculosis KatG and the isoniazid-resistant mutant KatG(S315T). Biochemistry 37, 15825–15834.[CrossRef]
    [Google Scholar]
  27. Wilson, T. M. & Collins, D. M. ( 1996; ). ahpC, a gene involved in isoniazid resistance of the Mycobacterium tuberculosis complex. Mol Microbiol 19, 1025–1034.[CrossRef]
    [Google Scholar]
  28. Yu, S., Girotto, S., Lee, C. & Magliozzo, R. S. ( 2003; ). Reduced affinity for isoniazid in the S315T mutant of Mycobacterium tuberculosis KatG is a key factor in antibiotic resistance. J Biol Chem 278, 14769–14775.[CrossRef]
    [Google Scholar]
  29. Zhang, Y. ( 2004; ). Isoniazid. In Tuberculosis, 2nd edn, pp. 739–758. Edited by W. N. Rom & S. M. Garay. New York: Lippincott Williams & Wilkins.
  30. Zhang, Y., Heym, B., Allen, B., Young, D. & Cole, S. ( 1992; ). The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358, 591–593.[CrossRef]
    [Google Scholar]
  31. Zhang, Y., Garbe, T. & Young, D. ( 1993; ). Transformation with katG restores isoniazid-sensitivity in Mycobacterium tuberculosis isolates resistant to a range of drug concentrations. Mol Microbiol 8, 521–524.[CrossRef]
    [Google Scholar]
  32. Zhang, Y., Vilchèze, C. & Jacobs, W. R. ( 2005; ). Mechanisms of drug resistance in Mycobacterium tuberculosis. In Tuberculosis and the Tubercle Bacillus, 2nd edn, pp. 115–140. Edited by S. T. Cole and others. Washington, DC: American Society for Microbiology.
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.46718-0
Loading
/content/journal/jmm/10.1099/jmm.0.46718-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error