23749189

PMC3777616

1 U54 GM088558/GM/NIGMS NIH HHS/United States
DP2 0D001378/DP/NCCDPHP CDC HHS/United States
DP2 OD001378/OD/NIH HHS/United States
T32 AI007638/AI/NIAID NIH HHS/United States
U19 AI076217/AI/NIAID NIH HHS/United States
U19 AI076217/AI/NIAID NIH HHS/United States
U54 GM088558/GM/NIGMS NIH HHS/United States
Howard Hughes Medical Institute/United States

CDC Public Access

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.