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Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes

Nature Genetics volume 44, pages 106–110 (2012)Cite this article

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Abstract

Epidemics of drug-resistant bacteria emerge worldwide, even as resistant strains frequently have reduced fitness compared to their drug-susceptible counterparts1. Data from model systems suggest that the fitness cost of antimicrobial resistance can be reduced by compensatory mutations2; however, there is limited evidence that compensatory evolution has any significant role in the success of drug-resistant bacteria in human populations3,4,5,6. Here we describe a set of compensatory mutations in the RNA polymerase genes of rifampicin-resistant M. tuberculosis, the etiologic agent of human tuberculosis (TB). M. tuberculosis strains harboring these compensatory mutations showed a high competitive fitness in vitro. Moreover, these mutations were associated with high fitness in vivo, as determined by examining their relative clinical frequency across patient populations. Of note, in countries with the world's highest incidence of multidrug-resistant (MDR) TB7, more than 30% of MDR clinical isolates had this form of mutation. Our findings support a role for compensatory evolution in the global epidemics of MDR TB8.

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Figure 1: Putative compensatory mutations in rpoA and rpoC of M. tuberculosis.
Figure 2: Putative compensatory mutations in rpoA and rpoC fall in regions encoding the interface of the RNA polymerase subunits.
Figure 3: Experimental and clinical relevance of putative compensatory mutations.

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Acknowledgements

We thank P. Small and C. Davis Long for stimulating discussions at the onset of this project, D. Young and M. Coscolla for reviewing the manuscript, A. Candel for advice in the interpretation of the RNA polymerase molecular structure and T. Van for technical support. We acknowledge the Wellcome Trust Sanger Institute for making available unpublished DNA sequence data (see URLs). We would like to thank T. Ubben, I. Razio and the other members of the German National Reference Center for Mycobateria for technical assistance and all partners that have contributed to previous studies in regions of high MDR TB incidence and collected some of the strains analyzed here. This project was funded wholly or in part by the US National Institute of Allergy and Infectious Disease, US National Institutes of Health and US Department of Health and Human Services (contract HHSN266200400001C, grants AI090928 and AI034238). This work was also supported by the Medical Research Council, UK (MRC_U117588500), the Swiss National Science Foundation (PP00A-119205) and the European Community LONG-DRUG (QLK-CT-2002-01612) and TB PAN-NET (FP7-223681) projects.

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  1. Iñaki Comas

    Present address: Current address: Genomics and Health Unit, Centre for Public Health Research, Valencia, Spain.,

Authors and Affiliations

  1. Division of Mycobacterial Research, Medical Research Council, National Institute for Medical Research, London, UK

    Iñaki Comas & Graham Rose

  2. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

    Sonia Borrell, Bijaya Malla & Sebastien Gagneux

  3. University of Basel, Basel, Switzerland

    Sonia Borrell, Bijaya Malla & Sebastien Gagneux

  4. Molecular Mycobacteriology, Research Centre Borstel, Borstel, Germany

    Andreas Roetzer & Stefan Niemann

  5. Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.,

    Midori Kato-Maeda

  6. The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA

    James Galagan

  7. Department of Microbiology, Boston University, Boston, Massachusetts, USA.,

    James Galagan

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Contributions

I.C., S.B. and S.G. planned the experiments. I.C., S.B., A.R., B.M., G.R., M.K.-M., J.G. and S.G. performed the experiments. I.C., S.B., A.R., G.R., S.N. and S.G. analyzed the data. I.C., S.B. and S.G. wrote the manuscript. All authors critically reviewed the manuscript.

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Correspondence to Sebastien Gagneux.

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The authors declare no competing financial interests.

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Comas, I., Borrell, S., Roetzer, A. et al. Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nat Genet 44, 106–110 (2012). https://doi.org/10.1038/ng.1038

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