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

Details

• Alternative Title:
  Nat Genet
• Personal Author:
  Ford, Christopher B. ; Shah, Rupal R. ; Maeda, Midori Kato ; Gagneux, Sebastien ; Murray, Megan B. ; Cohen, Ted ; Johnston, James C. ; Gardy, Jennifer ; Lipsitch, Marc ; Fortune, Sarah M.
• Description:
  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.
• Subjects:
  Antibiotics, Antitubercular Article Biomarkers, Pharmacological Communicable Diseases, Emerging Computer Simulation Drug Resistance, Multiple, Bacterial Genetic Speciation Humans Mutation Mutation Rate Mycobacterium Tuberculosis Prognosis Tuberculosis, Multidrug-Resistant

  More +
• Source:
  Nat Genet. 45(7):784-790.
• Pubmed ID:
  23749189
• Pubmed Central ID:
  PMC3777616
• Document Type:
  Journal Article
• Funding:
  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
• Volume:
  45
• Issue:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:4fdf6e2243dff90dce46a99996c83f75848ee4f837683201845dfc1f86000597
• Download URL:
  https://stacks.cdc.gov/view/cdc/22485/cdc_22485_DS1.pdf
• File Type:
  [PDF - 1.16 MB ]