title: Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis.
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.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Ford
authors.forename: Rupal R
authors.initials: RR
authors.lastname: Shah
authors.forename: Midori Kato
authors.initials: MK
authors.lastname: Maeda
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gagneux
authors.forename: Megan B
authors.initials: MB
authors.lastname: Murray
authors.forename: Ted
authors.initials: T
authors.lastname: Cohen
authors.forename: James C
authors.initials: JC
authors.lastname: Johnston
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gardy
authors.forename: Marc
authors.initials: M
authors.lastname: Lipsitch
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Fortune
mesh_terms: D000904:Antibiotics, Antitubercular / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis; D021821:Communicable Diseases, Emerging / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology*; D003198:Computer Simulation; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D049810:Genetic Speciation; D006801:Humans; D009154:Mutation / Q000502:physiology; D059645:Mutation Rate; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D011379:Prognosis; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology*
chemical_list: D000904:Antibiotics, Antitubercular; D054316:Biomarkers, Pharmacological