title: Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis.
abstract: Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter -15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P < 0.0001). Lineage 1 was associated with inhA promoter -15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P < 0.0001). In conclusion, M. tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance.
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. lfenner@ispm.unibe.ch
authors.forename: Lukas
authors.initials: L
authors.lastname: Fenner
authors.forename: Matthias
authors.initials: M
authors.lastname: Egger
authors.forename: Thomas
authors.initials: T
authors.lastname: Bodmer
authors.forename: Ekkehardt
authors.initials: E
authors.lastname: Altpeter
authors.forename: Marcel
authors.initials: M
authors.lastname: Zwahlen
authors.forename: Katia
authors.initials: K
authors.lastname: Jaton
authors.forename: Gaby E
authors.initials: GE
authors.lastname: Pfyffer
authors.forename: Sonia
authors.initials: S
authors.lastname: Borrell
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubuis
authors.forename: Thomas
authors.initials: T
authors.lastname: Bruderer
authors.forename: Hans H
authors.initials: HH
authors.lastname: Siegrist
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Calmy
authors.forename: Jan
authors.initials: J
authors.lastname: Fehr
authors.forename: Jesica Mazza
authors.initials: JM
authors.lastname: Stalder
authors.forename: Béatrice
authors.initials: B
authors.lastname: Ninet
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gagneux
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004977:Ethambutol / Q000494:pharmacology; D005838:Genotype; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D012293:Rifampin / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin