1887

Abstract

We report a case of chronic pulmonary multi-drug-resistant tuberculosis. Despite 14 years of treatment, was persistently isolated from sputum. Following treatment cessation the patient remained well, although was isolated from sputum for a further 8 years. Genome sequencing of eight serial isolates cultured between 1991 and 2011 revealed 17 mutations (0.8 mutations per genome year). Eight of these were persisting mutations and only two mutations were detected in the 7 years following cessation of treatment in 2004. In four isolates there were mixed alleles, suggesting the likely presence of bacterial subpopulations. The initial 1991 isolate demonstrated genotypic resistance to isoniazid ( W91R), rifampicin ( S531L), ethambutol ( M306V), streptomycin ( L16R), quinolones ( S95T) and P-aminosalicylic acid ( T202A). Subsequent resistance mutations developed for pyrazinamide ( I31F) and ethionamide ( frameshift). Such information might have been instructive when developing a treatment regimen. In retrospect and with the benefit of high-resolution genomic hindsight we were able to determine that the patient received only one or two active anti-tuberculous agents for most of their treatment. Additionally, mutations in and Rv2326c were detected, which may have contributed to the persistent but mild disease course. BacA is likely to be associated with maintenance of chronic infection and Rv2326c with a decreased bacterial metabolic state. These results expand our understanding of evolution during human infection and underline the link between antibiotic resistance and clinical persistence.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.
Loading

Article metrics loading...

/content/journal/mgen/10.1099/mgen.0.000037
2015-11-06
2021-10-27
Loading full text...

Full text loading...

/deliver/fulltext/mgen/1/5/mgen000037.html?itemId=/content/journal/mgen/10.1099/mgen.0.000037&mimeType=html&fmt=ahah

References

  1. Buchmeier N., Fahey R. C. 2006; The mshA gene encoding the glycosyltransferase of mycothiol biosynthesis is essential in Mycobacterium tuberculosis Erdman. FEMS Microbiol Lett 264:74–79 [View Article][PubMed]
    [Google Scholar]
  2. Coscolla M., Gagneux S. 2010; Does M. tuberculosis genomic diversity explain disease diversity?. Drug Discov Today Dis Mech 7:e43–e59 [View Article][PubMed]
    [Google Scholar]
  3. Domenech P., Kobayashi H., Lier K., Walker G. C., Barry C. E. III 2009; BacA, an ABC transporter involved in maintenance of chronic murine infections with Mycobacterium tuberculosis . J Bacteriol 191:477–485 [View Article][PubMed]
    [Google Scholar]
  4. Eldholm V., Norheim G., von der Lippe B., Kinander W., Dahle U. R., Caugant D. A., Mannsåker T., Mengshoel A. T., Dyrhol-Riise A. M., Balloux F. 2014; Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient. Genome Biol 15:490 [CrossRef]
    [Google Scholar]
  5. Ford C. B., Lin P. L., Chase M. R., Shah R. R., Iartchouk O., Galagan J., Mohaideen N., Ioerger T. R., Sacchettini J. C., other authors. 2011; Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet 43:482–486 [View Article][PubMed]
    [Google Scholar]
  6. Ford C. B., Shah R. R., Maeda M. K., Gagneux S., Murray M. B., Cohen T., Johnston J. C., Gardy J., Lipsitch M., Fortune S. M. 2013; Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet 45:784–790 [View Article][PubMed]
    [Google Scholar]
  7. Gagneux S., Long C. D., Small P. M., Van T., Schoolnik G. K., Bohannan B. J. 2006; The competitive cost of antibiotic resistance in Mycobacterium tuberculosis . Science 312:1944–1946 [View Article][PubMed]
    [Google Scholar]
  8. Gao W., Cameron D. R., Davies J. K., Kostoulias X., Stepnell J., Tuck K. L., Yeaman M. R., Peleg A. Y., Stinear T. P., Howden B. P. 2013; The RpoB H481Y rifampicin resistance mutation and an active stringent response reduce virulence and increase resistance to innate immune responses in Staphylococcus aureus . J Infect Dis 207:929–939 [View Article][PubMed]
    [Google Scholar]
  9. Glazebrook J., Ichige A., Walker G. C. 1993; Rhizobium meliloti homolog of the Escherichia coli peptide-antibiotic transport protein SbmA is essential for bacteroid development. Genes Dev 7:1485–1497 [View Article][PubMed]
    [Google Scholar]
  10. Hawkey J., Hamidian M., Wick R. R., Edwards D. J., Billman-Jacobe H., Hall R. M., Holt K. E. 2015; ISMapper: identifying transposase insertion sites in bacterial genomes from short read sequence data. BMC Genomics 16:667 [View Article][PubMed]
    [Google Scholar]
  11. Hillemann D., Hoffner S., Cirillo D., Drobniewski F., Richter E., Rüsch-Gerdes S., Baltic-Nordic TB-Laboratory Network, TB PAN-NET & ECDC ERLN-TB Networks. 2013; First evaluation after implementation of a quality control system for the second line drug susceptibility testing of Mycobacterium tuberculosis joint efforts in low and high incidence countries. PL One 8:e76765 [View Article][PubMed]
    [Google Scholar]
  12. Kapur V., Li L. L., Hamrick M. R., Plikaytis B. B., Shinnick T. M., Telenti A., Jacobs W.R. Jr, Banerjee A., Cole S., other authors. 1995; Rapid Mycobacterium species assignment and unambiguous identification of mutations associated with antimicrobial resistance in Mycobacterium tuberculosis by automated DNA sequencing. Arch Pathol Lab Med 119:131–138[PubMed]
    [Google Scholar]
  13. Lier K., Phillips R. W., Grippe V. K., Roop R.M. II, Walker G. C. 2000; Similar requirements of a plant symbiont and a mammalian pathogen for prolonged intracellular survival. Science 287:2492–2493 [View Article][PubMed]
    [Google Scholar]
  14. Li G., Zhang J., Guo Q., Wei J., Jiang Y., Zhao X., Zhao L. L., Liu Z., Lu J., Wan K. 2015; Study of efflux pump gene expression in rifampicin-monoresistant Mycobacterium tuberculosis clinical isolates. J Antibiot (Tokyo) 68:431–435 [View Article][PubMed]
    [Google Scholar]
  15. Mariam S. H., Werngren J., Aronsson J., Hoffner S., Andersson D. I. 2011; Dynamics of antibiotic resistant Mycobacterium tuberculosis during long-term infection and antibiotic treatment. PLoS One 6:e21147 [View Article][PubMed]
    [Google Scholar]
  16. Müller B., Borrell S., Rose G., Gagneux S. 2013; The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis . Trends Genet 29:160–169 [View Article][PubMed]
    [Google Scholar]
  17. Newton G. L., Ta P., Bzymek K. P., Fahey R. C. 2006; Biochemistry of the initial steps of mycothiol biosynthesis. J Biol Chem 281:33910–33920 [View Article][PubMed]
    [Google Scholar]
  18. Newton G. L., Buchmeier N., Fahey R. C. 2008; Biosynthesis and functions of mycothiol, the unique protective thiol of Actinobacteria. Microbiol Mol Biol Rev 72:471–494 [View Article][PubMed]
    [Google Scholar]
  19. Okamoto S., Tamaru A., Nakajima C., Nishimura K., Tanaka Y., Tokuyama S., Suzuki Y., Ochi K. 2007; Loss of a conserved 7-methylguanosine modification in 16S rRNA confers low-level streptomycin resistance in bacteria. Mol Microbiol 63:1096–1106 [View Article][PubMed]
    [Google Scholar]
  20. Rengarajan J., Sassetti C. M., Naroditskaya V., Sloutsky A., Bloom B. R., Rubin E. J. 2004; The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol 53:275–282 [View Article][PubMed]
    [Google Scholar]
  21. Ross B. C., Raios K., Jackson K., Sievers A., Dwyer B. 1991; Differentiation of Mycobacterium tuberculosis strains by use of a nonradioactive Southern blot hybridization method. J Infect Dis 163:904–907 [View Article][PubMed]
    [Google Scholar]
  22. Sandgren A., Strong M., Muthukrishnan P., Weiner B. K., Church G. M., Murray M. B. 2009; Tuberculosis Drug Resistance Mutation Database. PL Med 6:e1000002 [CrossRef]
    [Google Scholar]
  23. Sreevatsan S., Pan X., Zhang Y., Deretic V., Musser J. M. 1997a; Analysis of the oxyR-ahpC region in isoniazid-resistant and-susceptible Mycobacterium tuberculosis complex organisms recovered from diseased humans and animals in diverse localities. Antimicrob Agents Chemother 41:600–606[PubMed]
    [Google Scholar]
  24. Sreevatsan S., Stockbauer K. E., Pan X., Kreiswirth B. N., Moghazeh S. L., Jacobs W. R. Jr, Telenti A., Musser J. M. 1997b; Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 41:1677–1681[PubMed]
    [Google Scholar]
  25. Sun G., Luo T., Yang C., Dong X., Li J., Zhu Y., Zheng H., Tian W., Wang S., other authors. 2012; Dynamic population changes in Mycobacterium tuberculosis during acquisition and fixation of drug resistance in patients. J Infect Dis 206:1724–1733 [View Article][PubMed]
    [Google Scholar]
  26. Tiwari B. M., Kannan N., Vemu L., Raghunand T. R. 2012; The Mycobacterium tuberculosis PE proteins Rv0285 and Rv1386 modulate innate immunity and mediate bacillary survival in macrophages. PL One 7:e51686 [View Article][PubMed]
    [Google Scholar]
  27. Turcios L., Casart Y., Florez I., de Waard J., Salazar L. 2009; Characterization of IS6110 insertions in the dnaA-dnaN intergenic region of Mycobacterium tuberculosis clinical isolates. Clin Microbiol Infect 15:200–203 [View Article][PubMed]
    [Google Scholar]
  28. Vilchèze C., Av-Gay Y., Attarian R., Liu Z., Hazbón M. H., Colangeli R., Chen B., Liu W., Alland D., other authors. 2008; Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis . Mol Microbiol 69:1316–1329 [View Article][PubMed]
    [Google Scholar]
  29. Walker T. M., Kohl T. A., Omar S. V., Hedge J., Del Ojo Elias C., Bradley P., Iqbal Z., Feuerriegel S., Niehaus K. E., other authors. 2015; Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study. Lancet Infect Dis 15:1193–1202 [View Article][PubMed]
    [Google Scholar]
  30. Witney A. A., Gould K. A., Arnold A., Coleman D., Delgado R., Dhillon J., Pond M. J., Pope C. F., Planche T. D., other authors. 2015; Clinical application of whole-genome sequencing to inform treatment for multidrug-resistant tuberculosis cases. J Clin Microbiol 53:1473–1483 [View Article][PubMed]
    [Google Scholar]
  31. Yousuf S., Angara R., Vindal V., Ranjan A. 2015; Rv0494 is a starvation-inducible, auto-regulatory Fa-like regulator from Mycobacterium tuberculosis . Microbiology 161:463–476 [View Article][PubMed]
    [Google Scholar]
  32. Zaunbrecher M. A., Sikes R. D. Jr, Metchock B., Shinnick T. M., Posey J. E. 2009; Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis . Proc Natl Acad Sci U S A 106:20004–20009 [View Article][PubMed]
    [Google Scholar]
  33. Zetola N. M., Modongo C., Moonan P. K., Ncube R., Matlhagela K., Sepako E., Collman R. G., Bisson G. P. 2014; Clinical outcomes among persons with pulmonary tuberculosis caused by Mycobacterium tuberculosis isolates with phenotypic heterogeneity in results of drug-susceptibility tests. J Infect Dis 209:1754–1763 [View Article][PubMed]
    [Google Scholar]
  34. Stinear, T. European Nucleotide Archive (ENA) http://www.ebi.ac.uk/ena/data/view/ERP011175 (2015).
http://instance.metastore.ingenta.com/content/journal/mgen/10.1099/mgen.0.000037
Loading
/content/journal/mgen/10.1099/mgen.0.000037
Loading

Data & Media loading...

Supplements

Loading data from figshare Loading data from figshare

Most cited this month Most Cited RSS feed

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