title: Gyrase Mutations Are Associated with Variable Levels of Fluoroquinolone Resistance in Mycobacterium tuberculosis.
abstract: Molecular diagnostics that rapidly and accurately predict resistance to fluoroquinolone drugs and especially later-generation agents promise to improve treatment outcomes for patients with multidrug-resistant tuberculosis and prevent the spread of disease. Mutations in the gyr genes are known to confer most fluoroquinolone resistance, but knowledge about the effects of gyr mutations on susceptibility to early- versus later-generation fluoroquinolones and about the role of mutation-mutation interactions is limited. Here, we sequenced the full gyrA and gyrB open reading frames in 240 multidrug-resistant and extensively drug-resistant tuberculosis strains and quantified their ofloxacin and moxifloxacin MIC by testing growth at six concentrations for each drug. We constructed a multivariate regression model to assess both the individual mutation effects and interactions on the drug MICs. We found that gyrB mutations contribute to fluoroquinolone resistance both individually and through interactions with gyrA mutations. These effects were statistically significant. In these clinical isolates, several gyrA and gyrB mutations conferred different levels of resistance to ofloxacin and moxifloxacin. Consideration of gyr mutation combinations during the interpretation of molecular test results may improve the accuracy of predicting the fluoroquinolone resistance phenotype. Further, the differential effects of gyr mutations on the activity of early- and later-generation fluoroquinolones requires further investigation and could inform the selection of a fluoroquinolone for treatment.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA mrfarhat@partners.org.
authors.forename: Maha R
authors.initials: MR
authors.lastname: Farhat
authors.affiliation: Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, USA DST/NRF Centre of Excellence for Biomedical TB Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Jacobson
authors.affiliation: Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Molly F
authors.initials: MF
authors.lastname: Franke
authors.affiliation: University of Massachusetts Medical School, Massachusetts Supranational TB Reference Laboratory, Boston, Massachusetts, USA.
authors.forename: Devinder
authors.initials: D
authors.lastname: Kaur
authors.affiliation: University of Massachusetts Medical School, Massachusetts Supranational TB Reference Laboratory, Boston, Massachusetts, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Sloutsky
authors.affiliation: Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA Department of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Carole D
authors.initials: CD
authors.lastname: Mitnick
authors.affiliation: Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Murray
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology; D027081:DNA Gyrase / Q000235:genetics*; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D059645:Mutation Rate; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D024841:Fluoroquinolones; D027081:DNA Gyrase