Abstract

The molecular mechanisms determining the transmissibility and prevalence of drug-resistant tuberculosis in a population were investigated through whole-genome sequencing of 1,000 prospectively obtained patient isolates from Russia. Two-thirds belonged to the Beijing lineage, which was dominated by two homogeneous clades. Multidrug-resistant (MDR) genotypes were found in 48% of isolates overall and in 87% of the major clades. The most common rpoB mutation was associated with fitness-compensatory mutations in rpoA or rpoC, and a new intragenic compensatory substitution was identified. The proportion of MDR cases with extensively drug-resistant (XDR) tuberculosis was 16% overall, with 65% of MDR isolates harboring eis mutations, selected by kanamycin therapy, which may drive the expansion of strains with enhanced virulence. The combination of drug resistance and compensatory mutations displayed by the major clades confers clinical resistance without compromising fitness and transmissibility, showing that, in addition to weaknesses in the tuberculosis control program, biological factors drive the persistence and spread of MDR and XDR tuberculosis in Russia and beyond.

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Acknowledgements

We are grateful to members of the Public Health England National Mycobacterium Reference Laboratory and the Samara Regional Tuberculosis Laboratory for bacteriological work, particularly M. Stone, X. Gonzalo and A. Broda. We would also like to thank the Samara Tuberculosis Service, particularly I. Fedorin, as well as V. Kulichenko. We thank R. Hooper for expert statistical advice, S. Hoffner for bacteriological advice and S. Bentley for sequencing advice. This study was supported by European Union Framework Programme 7 (grant 201483; TB-EUROGEN), with sequencing funded by the Wellcome Trust (grant 098051) and EUROGEN. S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z) and is also supported by European Research Council Starting Grant 260477.

Author information

Affiliations

  1. Public Health England (PHE) National Mycobacterium Reference Laboratory, Clinical TB and HIV Group, Blizard Institute, Queen Mary University of London, London, UK.

    • Nicola Casali
    • , Vladyslav Nikolayevskyy
    • , Yanina Balabanova
    • , Timothy Brown
    •  & Francis Drobniewski
  2. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Simon R Harris
    • , Josephine Bryant
    •  & Julian Parkhill
  3. Samara Oblast Tuberculosis Dispensary, Samara, Russian Federation.

    • Olga Ignatyeva
    •  & Irina Kontsevaya
  4. Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.

    • Jukka Corander
  5. Department of Medicine, University of Cambridge, Cambridge, UK.

    • Sergey Nejentsev
  6. Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

    • Rolf D Horstmann
  7. Department of Infectious Diseases, Imperial College, London, UK.

    • Francis Drobniewski

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Contributions

N.C., V.N., Y.B. and F.D. designed the study. O.I., I.K., V.N. and Y.B. recruited patients and collected epidemiological data. O.I. and I.K. performed laboratory work. N.C., S.R.H. and J.C. conducted sequence analysis. N.C., T.B., V.N. and F.D. interpreted the data. Y.B., O.I. and F.D. performed statistical comparisons. N.C. and F.D. drafted the manuscript. T.B., V.N., Y.B., O.I., I.K., S.R.H., J.P., J.B., S.N. and R.D.H. provided critical analysis and reviewed the manuscript. All authors approved the final draft.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Francis Drobniewski.

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    Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Tables 1–3 and 5–11

Text files

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    Supplementary Data Set 1

    Maximum likelihood phylogeny of 1,035 M. tuberculosis isolates based on 32,445 variable sites

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    Supplementary Table 4

    Polymorphisms at drug resistance loci

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DOI

https://doi.org/10.1038/ng.2878

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