A key question in tuberculosis control is why some strains of M. tuberculosis are preferentially associated with resistance to multiple drugs. We demonstrate that M. tuberculosis strains from lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole-genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug-susceptible lineage 2 strain will harbor multidrug-resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug-resistant tuberculosis should target bacterial as well as treatment-related risk factors.
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This work was supported by a New Innovator's Award (DP2 0D001378) from the Director's Office of the US National Institutes of Health (S.M.F.), by a subcontract from the National Institute of Allergy and Infectious Diseases (U19 AI076217 to S.M.F. and M.B.M.), by the US National Institutes of Health Models of Infectious Disease Agent Study program, through cooperative agreement 1 U54 GM088558 (M.L.), by a Howard Hughes Medical Institute Physician Scientist Early Career Award (S.M.F.), by a Merit Fellowship from the Harvard University Graduate School of Arts and Sciences (C.B.F.) and by a Doris Duke Charitable Foundation Clinical Scientist Development Award (S.M.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases or the US National Institutes of Health.
The authors declare no competing financial interests.
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Ford, C., Shah, R., Maeda, M. et al. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet 45, 784–790 (2013). https://doi.org/10.1038/ng.2656
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