title: Longitudinal whole genome analysis of pre and post drug treatment Mycobacterium tuberculosis isolates reveals progressive steps to drug resistance.
abstract: 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.
authors.affiliation: Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA; Computational Bioscience Program, University of Colorado, Denver, School of Medicine, Aurora, CO 80045, USA. Electronic address: gargi.datta@ucdenver.edu.
authors.forename: Gargi
authors.initials: G
authors.lastname: Datta
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Electronic address: luisa.nieto_ramirez@colostate.edu.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Nieto
authors.affiliation: Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA. Electronic address: davidsonr@njhealth.org.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Davidson
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Electronic address: carolina.mehaffy@colostate.edu.
authors.forename: Carolina
authors.initials: C
authors.lastname: Mehaffy
authors.affiliation: ATCC, 10801 University Boulevard, Manassas, VA 20110, USA. Electronic address: cpederson@atcc.org.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pederson
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Electronic address: karen.dobos@colostate.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dobos
authors.affiliation: Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA; Computational Bioscience Program, University of Colorado, Denver, School of Medicine, Aurora, CO 80045, USA. Electronic address: strongm@njhealth.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Strong
mesh_terms: D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics; D002374:Catalase / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D016680:Genome, Bacterial; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D012293:Rifampin / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; D007538:Isoniazid; D012293:Rifampin
keywords: Drug resistance progression; Isoniazid; Mycobacterium tuberculosis; Rifampin; Single nucleotide polymorphism; Whole genome sequencing