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Clinically prevalent mutations in Mycobacterium tuberculosis alter propionate metabolism and mediate multidrug tolerance

Nature Microbiology volume 3, pages 1032–1042 (2018)Cite this article

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Abstract

The global epidemic of drug-resistant tuberculosis is a catastrophic example of how antimicrobial resistance is undermining the public health gains made possible by combination drug therapy. Recent evidence points to unappreciated bacterial factors that accelerate the emergence of drug resistance. In a genome-wide association study of Mycobacterium tuberculosis isolates from China, we find mutations in the gene encoding the transcription factor prpR enriched in drug-resistant strains. prpR mutations confer conditional drug tolerance to three of the most effective classes of antibiotics by altering propionyl-CoA metabolism. prpR-mediated drug tolerance is carbon-source dependent, and while readily detectable during infection of human macrophages, is not captured by standard susceptibility testing. These data define a previously unrecognized and clinically prevalent class of M. tuberculosis variants that undermine antibiotic efficacy and drive drug resistance.

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Fig. 1: Genetic associations with isoniazid resistance.
Fig. 2: Distribution and functional characterization of prpR mutants.
Fig. 3: prpR mutants display conditional multidrug tolerance.
Fig. 4: Infection of human macrophages induces multidrug tolerance in prpR mutants.
Fig. 5: Metabolic rescue of propionate sensitivity suppresses drug tolerance in prpR mutants.

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Acknowledgements

Support was generously provided by the National Major Science and Technology Project of China (2012ZX10003002001-001; 2014ZX10003002) to Y.Z.; the National Program on Key Basic Research Project of China (2014CB744403973) and the CAMS Innovation Fund for Medical Sciences (2016-I2M-1-013) to Q.J.; the National Institute of Health (5U19AI109755-04) to S.M.F.; and NIH pre-doctoral training grant support (5T32AI007638-15 to E. J. Rubin and 5T32-AI049928-14 to D. Wirth) to N.D.H.

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Author notes

  1. These authors contributed equally to this work: Nathan D. Hicks, Jian Yang, Xiaobing Zhang, Bing Zhao.

Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Nathan D. Hicks, Yonatan H. Grad & Sarah M. Fortune

  2. MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Centre for Tuberculosis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Jian Yang, Xiaobing Zhang, Liguo Liu, Zhili Chang, Jie Dong, Lilian Sun, Yafang Zhu & Qi Jin

  3. National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

    Bing Zhao, Xichao Ou, Hui Xia, Yang Zhou, Shengfen Wang & Yanlin Zhao

  4. Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Yonatan H. Grad

  5. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA

    Sarah M. Fortune

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Contributions

X.Z., B.Z., X.C.O., S.F.W., H.X. and Y. Zhou were responsible for cohort study and strain set assembly. Q.J. and Y. Zhao were responsible for genome sequencing study design and supervision. J.Y., X.Z., L.L., Z.C., J.D., L.S. and Y. Zhu were responsible for genome sequencing and variant analysis. N.D.H., J.Y., Y.G. and S.M.F. were responsible for genome-wide association study. N.D.H. and S.M.F. were responsible for experimental validation. N.D.H., J.Y. and S.M.F. were responsible for manuscript preparation.

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Correspondence to Yanlin Zhao, Qi Jin or Sarah M. Fortune.

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Hicks, N.D., Yang, J., Zhang, X. et al. Clinically prevalent mutations in Mycobacterium tuberculosis alter propionate metabolism and mediate multidrug tolerance. Nat Microbiol 3, 1032–1042 (2018). https://doi.org/10.1038/s41564-018-0218-3

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