Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA.
Nat Genet. 2013 Jul;45(7):784-90. doi: 10.1038/ng.2656. Epub 2013 Jun 9.
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.
结核病控制中的一个关键问题是，为什么有些结核分枝杆菌菌株更容易对多种药物产生耐药性。我们证明了来自谱系 2（东亚谱系和北京亚型）的结核分枝杆菌菌株在体外比来自谱系 4（欧洲-美洲谱系）的结核分枝杆菌菌株更容易获得耐药性，而这种更高的速率可以归因于更高的突变率。此外，体外突变率与通过对临床分离株进行全基因组测序确定的人类细菌突变率密切相关。最后，使用随机数学模型，我们证明观察到的突变率差异预测了一个更高的概率，即在诊断时，感染耐药性谱系 2 菌株的患者将携带耐多药细菌。这些数据表明，预防耐药性结核病出现的干预措施应针对细菌和与治疗相关的风险因素。
