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Nat Genet. 2013 Jul;45(7):784-90. doi: 10.1038/ng.2656. Epub 2013 Jun 9.

Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis.

Author information

1
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA.

Abstract

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.

PMID:
23749189
PMCID:
PMC3777616
DOI:
10.1038/ng.2656
[Indexed for MEDLINE]
Free PMC Article

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