1887

Abstract

The phenotypic resistance to ethambutol (EMB) in with gene mutations is still unclear. This study was designed to better understand EMB resistance due to gene mutation. Sequencing analysis of the gene was performed for 124 EMB-susceptible and 93 EMB-resistant strains isolated from South Korea. The MIC was determined for EMB-susceptible strains with the mutation and wild-type on Löwenstein–Jenson (LJ) solid medium in duplicate. Two (2.8 %) of 72 pan-susceptible, two (9.1 %) of 22 any-drug-resistant but EMB-susceptible, nine (30.0 %) of 30 multidrug-resistant (MDR) but EMB-susceptible and 84 (90.3 %) of 93 EMB-resistant strains possessed mutations at various codons including 306, 319, 354, 360, 399, 405, 406, 459 and 497. Strains with mutations at codons 306, 354, 399, 405 and 497 had highly pronounced EMB resistance, while strains with mutations at codons 319 and 406 mutations were moderately resistant and those with an mutation were EMB-susceptible at the critical concentration (2.0 µg ml) on LJ solid medium. However, the mean MIC for strains with mutations (1.42 µg ml) was higher than that for strains without the mutation (1.0 µg ml) in EMB-susceptible isolates ( = 0.0052). Three novel mutations at codons 399, 405 and 459 were identified in this study. These results support the hypothesis that mutation except for a few specific mutation types may be the main cause of EMB resistance.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.037614-0
2012-04-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jmm/61/4/529.html?itemId=/content/journal/jmm/10.1099/jmm.0.037614-0&mimeType=html&fmt=ahah

References

  1. Alcaide F., Pfyffer G. E., Telenti A. 1997; Role of embB in natural and acquired resistance to ethambutol in mycobacteria. Antimicrob Agents Chemother 41:2270–2273[PubMed]
    [Google Scholar]
  2. Canetti G., Fox W., Khomenko A., Mahler H. T., Menon N. K., Mitchison D. A., Rist N., Smelev N. A. 1969; Advances in techniques of testing mycobacterial drug sensitivity, and the use of sensitivity tests in tuberculosis control programmes. Bull World Health Organ 41:21–43[PubMed]
    [Google Scholar]
  3. CDC 2006; Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs – worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep 55:301–305[PubMed]
    [Google Scholar]
  4. Cole S. T., Brosch R., Parkhill J., Garnier T., Churcher C., Harris D., Gordon S. V., Eiglmeier K., Gas S. other authors 1998; Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544 [View Article][PubMed]
    [Google Scholar]
  5. Hazbón M. H., Bobadilla del Valle M., Guerrero M. I., Varma-Basil M., Filliol I., Cavatore M., Colangeli R., Safi H., Billman-Jacobe H. other authors 2005; 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 49:3794–3802 [View Article][PubMed]
    [Google Scholar]
  6. Kemper C. A., Havlir D., Haghighat D., Dubé M., Bartok A. E., Sison J. P., Yao Y., Yangco B., Leedom J. M. other authors 1994; The individual microbiologic effect of three antimycobacterial agents, clofazimine, ethambutol, and rifampin, on Mycobacterium avium complex bacteremia in patients with AIDS. J Infect Dis 170:157–164 [View Article][PubMed]
    [Google Scholar]
  7. Kim S. J. 2005; Drug-susceptibility testing in tuberculosis: methods and reliability of results. Eur Respir J 25:564–569 [View Article][PubMed]
    [Google Scholar]
  8. Lee A. S., Othman S. N., Ho Y. M., Wong S. Y. 2004; Novel mutations within the embB gene in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 48:4447–4449 [View Article][PubMed]
    [Google Scholar]
  9. Migliori G. B., Loddenkemper R., Blasi F., Raviglione M. C. 2007; 125 years after Robert Koch’s discovery of the tubercle bacillus: the new XDR-TB threat. Is “science” enough to tackle the epidemic?. Eur Respir J 29:423–427 [View Article][PubMed]
    [Google Scholar]
  10. Mokrousov I., Otten T., Vyshnevskiy B., Narvskaya O. 2002; Detection of embB306 mutations in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis from Northwestern Russia: implications for genotypic resistance testing. J Clin Microbiol 40:3810–3813 [View Article][PubMed]
    [Google Scholar]
  11. Morris S., Bai G. H., Suffys P., Portillo-Gomez L., Fairchok M., Rouse D. 1995; Molecular mechanisms of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis.. J Infect Dis 171:954–960 [View Article][PubMed]
    [Google Scholar]
  12. Musser J. M. 1995; Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev 8:496–514[PubMed]
    [Google Scholar]
  13. Park Y. K., Bai G. H., Kim S. J. 2000; Restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolated from countries in the western pacific region. J Clin Microbiol 38:191–197[PubMed]
    [Google Scholar]
  14. Plinke C., Rüsch-Gerdes S., Niemann S. 2006; Significance of mutations in embB codon 306 for prediction of ethambutol resistance in clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 50:1900–1902 [View Article][PubMed]
    [Google Scholar]
  15. Rabarijaona L., Boisier P., Ratsirahonana O., Razafinimanana J., Rakotomanana F., Ratsitorahina M., Ramarokoto H., Cauchoix B., Aurégan G. 1999; Replacement of streptomycin by ethambutol in the intensive phase of tuberculosis treatment: no effect on compliance. Int J Tuberc Lung Dis 3:42–46[PubMed]
    [Google Scholar]
  16. Ramaswamy S. V., Musser J. M. 1998; Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 79:3–29 [View Article][PubMed]
    [Google Scholar]
  17. Ramaswamy S. V., Dou S. J., Rendon A., Yang Z., Cave M. D., Graviss E. A. 2004; Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey, Mexico. J Med Microbiol 53:107–113 [View Article][PubMed]
    [Google Scholar]
  18. Raviglione M. C., Smith I. M. 2007; XDR tuberculosis – implications for global public health. N Engl J Med 356:656–659 [View Article][PubMed]
    [Google Scholar]
  19. Safi H., Sayers B., Hazbón M. H., Alland D. 2008; Transfer of embB codon 306 mutations into clinical Mycobacterium tuberculosis strains alters susceptibility to ethambutol, isoniazid, and rifampin. Antimicrob Agents Chemother 52:2027–2034 [View Article][PubMed]
    [Google Scholar]
  20. Safi H., Fleischmann R. D., Peterson S. N., Jones M. B., Jarrahi B., Alland D. 2010; Allelic exchange and mutant selection demonstrate that common clinical embCAB gene mutations only modestly increase resistance to ethambutol in Mycobacterium tuberculosis. Antimicrob Agents Chemother 54:103–108 [View Article][PubMed]
    [Google Scholar]
  21. Sekiguchi J., Miyoshi-Akiyama T., Augustynowicz-Kopeć E., Zwolska Z., Kirikae F., Toyota E., Kobayashi I., Morita K., Kudo K. other authors 2007; Detection of multidrug resistance in Mycobacterium tuberculosis. J Clin Microbiol 45:179–192 [View Article][PubMed]
    [Google Scholar]
  22. Shen X., Shen G. M., Wu J., Gui X. H., Li X., Mei J., DeRiemer K., Gao Q. 2007; Association between embB codon 306 mutations and drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 51:2618–2620 [View Article][PubMed]
    [Google Scholar]
  23. Shi R., Zhang J., Otomo K., Zhang G., Sugawara I. 2007; Lack of correlation between embB mutation and ethambutol MIC in Mycobacterium tuberculosis clinical isolates from China. Antimicrob Agents Chemother 51:4515–4517 [View Article][PubMed]
    [Google Scholar]
  24. Shi D., Li L., Zhao Y., Jia Q., Li H., Coulter C., Jin Q., Zhu G. 2011; Characteristics of embB mutations in multidrug-resistant Mycobacterium tuberculosis isolates in Henan, China. J Antimicrob Chemother 66:2240–2247 [View Article][PubMed]
    [Google Scholar]
  25. Sreevatsan S., Stockbauer K. E., Pan X., Kreiswirth B. N., Moghazeh S. L., Jacobs W. R. Jr, Telenti A., Musser J. M. 1997; Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 41:1677–1681[PubMed]
    [Google Scholar]
  26. Srivastava S., Ayyagari A., Dhole T. N., Nyati K. K., Dwivedi S. K. 2009; emb nucleotide polymorphisms and the role of embB306 mutations in Mycobacterium tuberculosis resistance to ethambutol. Int J Med Microbiol 299:269–280 [View Article][PubMed]
    [Google Scholar]
  27. Starks A. M., Gumusboga A., Plikaytis B. B., Shinnick T. M., Posey J. E. 2009; Mutations at embB codon 306 are an important molecular indicator of ethambutol resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 53:1061–1066 [View Article][PubMed]
    [Google Scholar]
  28. Sugawara I., Otomo K., Yamada H., Wang G., Du C., Shi R., Zhang G. 2005; The molecular epidemiology of ethambutol-resistant Mycobacterium tuberculosis in Henan Province, China. Jpn J Infect Dis 58:393–395[PubMed]
    [Google Scholar]
  29. Telenti A., Philipp W. J., Sreevatsan S., Bernasconi C., Stockbauer K. E., Wieles B., Musser J. M., Jacobs W. R. Jr 1997; The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med 3:567–570 [View Article][PubMed]
    [Google Scholar]
  30. Van Rie A., Warren R., Mshanga I., Jordaan A. M., van der Spuy G. D., Richardson M., Simpson J., Gie R. P., Enarson D. A. other authors 2001; Analysis for a limited number of gene codons can predict drug resistance of Mycobacterium tuberculosis in a high-incidence community. J Clin Microbiol 39:636–641 [View Article][PubMed]
    [Google Scholar]
  31. WHO 1997; Treatment of Tuberculosis. Guidelines for the Management of Drug-resistant Tuberculosis, 2nd edn, pp. 1–47. Geneva: World Health Organization;
  32. WHO 2009; Global Tuberculosis Control 2009: Epidemiology Strategy Financing. Report No. WHO/HTM/TB/2009.411, pp. 1–303. Geneva: World Health Organization;
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.037614-0
Loading
/content/journal/jmm/10.1099/jmm.0.037614-0
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