Journal
NATURE MICROBIOLOGY
Volume 3, Issue 9, Pages 1032-1042Publisher
NATURE RESEARCH
DOI: 10.1038/s41564-018-0218-3
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Funding
- National Major Science and Technology Project of China [2012ZX10003002001-001, 2014ZX10003002]
- National Program on Key Basic Research Project of China [2014CB744403973]
- CAMS Innovation Fund for Medical Sciences [2016-I2M-1-013]
- National Institute of Health [5U19AI109755-04]
- NIH [5T32AI007638-15, 5T32-AI049928-14]
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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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