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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Global Tuberculosis Report 2017 (WHO, 2017); http://www.who.int/tb/publications/global_report/gtbr2017_main_text.pdf
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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.
The authors declare no competing interests.
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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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