Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

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We would like to thank the Broad Institute's Genome Sequencing Platform and Assembly and Annotation teams, including S.K. Young, M.E. Priest, T.P. Shea, B.J. Walker, L. Alvarado, M.G. Fitzgerald, S. Gujja, S. Hamilton, C. Howarth, J.D. Larimer, M.D. Pearson, Q. Zeng and J. Wortman. We would like to thank J. Romano and A. Keo for help with lineage detection, and M. Zambrano, B. Ferro and J.C. Rozo for isolation and phenotypic characterization of strains. We are also grateful to members of the TBResist Consortium for contribution of their strains, phenotypic data and expertise, and their help in forging collaborations, and to V. Dartois, D. Thomas, D. Hung and D. Plachetzki for helpful conversations. We also thank three anonymous reviewers of our manuscript for their insights and helpful suggestions. This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services (grant U19AI110818 to the Broad Institute (B.W.B. and A.M.E.)), contract HHSN272200900018C to the Broad Institute (B.W.B.) and contract HHSN2722000900050C to the TB Clinical Diagnostics Research Consortium, the Intramural Research Program of NIAID (C.E.B. and L.E.V.) and the Korean CDC, Korean Ministry of Health and Welfare. This work was also funded (in part) by the intramural research program of the NIAID, NIH (C.E.B.). Funding was also provided by NIH grant 5U01AI069924-07 for IeDEA (A.S.P.), the Howard Hughes Medical Institute (W.R.B.) and NIH grant R01 AI110386 for 'Host–pathogen interactions in a failing global lineage of MTBC: M. africanum' (W.R.B.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Author information

Author notes

    • Abigail L Manson
    •  & Keira A Cohen

    These authors contributed equally to this work.


  1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Abigail L Manson
    • , Keira A Cohen
    • , Thomas Abeel
    • , Christopher A Desjardins
    • , Sinéad B Chapman
    • , James Gomez
    • , Alex Salazar
    • , James E Galagan
    • , Bruce W Birren
    •  & Ashlee M Earl
  2. KwaZulu-Natal Research Institute for TB and HIV (K-RITH), Durban, South Africa.

    • Keira A Cohen
    • , Alexander S Pym
    •  & William R Bishai
  3. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Keira A Cohen
  4. Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands.

    • Thomas Abeel
    •  & Alex Salazar
  5. Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.

    • Derek T Armstrong
    • , Kathryn Winglee
    • , Susan E Dorman
    •  & William R Bishai
  6. National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.

    • Clifton E Barry III
    •  & Laura E Via
  7. Medical Research Council, TB Platform, Pretoria, South Africa.

    • Jeannette Brand
    • , Lesibana Malinga
    •  & Martie Van der Walt
  8. International Tuberculosis Research Center, Changwon and Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.

    • Sang-Nae Cho
    •  & Jong Seok Lee
  9. Office of Cyber Infrastructure and Computational Biology, National Institutes of Health, Rockville, Maryland, USA.

    • Andrei Gabrielian
    •  & Alex Rosenthal
  10. Clinical Hospital of Pneumology Leon Daniello, Cluj Napoca, Romania.

    • Daniela Homorodean
    •  & Andreea M Jodals
  11. Department of Medical Microbiology, Mycobacteriology Laboratory, Makerere University, Kampala, Uganda.

    • Moses Joloba
    •  & Willy Ssengooba
  12. Public Health Agency of Sweden, Solna, Sweden.

    • Pontus Jureen
    •  & Sven Hoffner
  13. University of Sciences, Techniques and Technologies of Bamako (USTTB), Bamako, Mali.

    • Mamoudou Maiga
  14. Novasano Health and Science, New York, New York, USA.

    • Dale Nordenberg
  15. Microbiology and Morphology Laboratory, Phthisiopneumology Institute, Chisinau, Moldova.

    • Ecaterina Noroc
    • , Elena Romancenco
    •  & Valeriu Crudu
  16. Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

    • A A Velayati
    •  & Parissa Farnia
  17. Republican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.

    • Aksana Zalutskaya
    •  & Alena Skrahina
  18. Department of Global Health and Social Medicine, Harvard Medical School, Division of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Gail H Cassell
  19. Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA.

    • Jerrold Ellner
  20. Department of Biomedical Engineering and Microbiology, Boston University, Boston, Massachusetts, USA.

    • James E Galagan
  21. National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

    • Po-Ren Hsueh
  22. National Institute for Research in Tuberculosis, Chennai, India.

    • Sujatha Narayanan
    •  & Soumya Swaminathan
  23. Rutgers–New Jersey Medical School, Newark, New Jersey, USA.

    • David Alland
  24. Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Ted Cohen
  25. Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.

    • Ted Cohen


  1. TBResist Global Genome Consortium


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A.L.M., K.A.C., T.A., C.A.D., B.W.B. and A.M.E. conceived the project; A.L.M., K.A.C., T.A., C.A.D. and A. Salazar analyzed the data; A.L.M., K.A.C. and A.M.E. interpreted results; A.L.M. and K.A.C. wrote the manuscript; and D.T.A., C.E.B., J.B., S.B.C., S.-N.C., A.G., J.G., A.M.J., M.J., P.J., J.S.L., L.M., M.M., D.N., E.N., E.R., A. Skrahina, W.S., A.A.V., K.W., A.Z., L.E.V., G.H.C., S.E.D., J.E., P.F., J.E.G., A.R., V.C., D.H., P.-R.H., S.N., A.S.P., S.S., M.V.d.W., D.A., W.R.B., T.C. and S.H. were involved in sample acquisition and handling, including oversight of these activities. All authors critically read and revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ashlee M Earl.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11, Supplementary Tables 1, 3, 4, 6 and 8–13, and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 2

    List of 5,310 strains included in our final data set of sequenced M. tuberculosis clinical isolates.

  2. 2.

    Supplementary Table 5

    List of all 392 mutations in our data set and their frequencies, as well as their frequencies of occurring first.

  3. 3.

    Supplementary Table 7

    The number of arisals and the number of strains with each mutation, for each of the 11 geographical regions with >30 strains.

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