Longitudinal whole genome analysis of pre and post drug treatment Mycobacterium tuberculosis isolates reveals progressive steps to drug resistance

Tuberculosis (Edinb). 2016 May;98:50-5. doi: 10.1016/j.tube.2016.02.004. Epub 2016 Feb 26.


Tuberculosis (TB) is one of the leading causes of death due to an infectious disease in the world. Understanding the mechanisms of drug resistance has become pivotal in the detection and treatment of newly emerging resistant TB cases. We have analyzed three pairs of Mycobacterium tuberculosis strains pre- and post-drug treatment to identify mutations involved in the progression of resistance to the drugs rifampicin and isoniazid. In the rifampicin resistant strain, we confirmed a mutation in rpoB (S450L) that is known to confer resistance to rifampicin. We discovered a novel L101R mutation in the katG gene of an isoniazid resistant strain, which may directly contribute to isoniazid resistance due to the proximity of the mutation to the katG isoniazid-activating site. Another isoniazid resistant strain had a rare mutation in the start codon of katG. We also identified a number of mutations in each longitudinal pair, such as toxin-antitoxin mutations that may influence the progression towards resistance or may play a role in compensatory fitness. These findings improve our knowledge of drug resistance progression during therapy and provide a methodology to monitor longitudinal strains using whole genome sequencing, polymorphism comparison, and functional annotation.

Keywords: Drug resistance progression; Isoniazid; Mycobacterium tuberculosis; Rifampin; Single nucleotide polymorphism; Whole genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / therapeutic use*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Toxins / chemistry
  • Bacterial Toxins / genetics
  • Catalase / chemistry
  • Catalase / genetics
  • DNA Mutational Analysis
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Genome, Bacterial*
  • Genotype
  • Humans
  • Isoniazid / therapeutic use
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mutation*
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / pathogenicity
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protein Conformation
  • Rifampin / therapeutic use
  • Structure-Activity Relationship
  • Time Factors
  • Treatment Outcome
  • Tuberculosis / diagnosis
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Bacterial Proteins
  • Bacterial Toxins
  • Catalase
  • katG protein, Mycobacterium tuberculosis
  • Isoniazid
  • Rifampin