title: Impaired fitness of Mycobacterium tuberculosis resistant isolates in a cell culture model of murine macrophages.
abstract: OBJECTIVE
  We analysed the ability of Mycobacterium tuberculosis clinical isolates to penetrate and grow inside murine macrophages as a surrogate of fitness.
  
  
  METHODS
  Thirty-five drug-resistant and 10 drug-susceptible M. tuberculosis isolates were studied in a murine macrophage model from the J774.2 cell line in a 6 day protocol, performing semi-quantitative counts in Middlebrook 7H11 medium. The mycobacterial penetration index (MPI) after infection and the mycobacterial growth ratio (MGR) inside the macrophages were determined to evaluate the fitness of isolates.
  
  
  RESULTS
  Isolates with the katG S315T mutation and multidrug-resistant (MDR) isolates had a significantly lower MGR compared with drug-susceptible isolates. The MPI of the isolates with the katG S315T mutation showed a significant decrease compared with the MPI of those without this mutation. A trend to significantly lower values was also observed on comparing the MPI of the MDR isolates with that of the drug-susceptible isolates and the isolates resistant to isoniazid.
  
  
  CONCLUSIONS
  The isoniazid-resistant and MDR isolates with mutations in the katG gene showed decreased multiplication inside murine macrophages, suggesting a lower fitness of M. tuberculosis with these resistance patterns.
authors.affiliation: Servei de Microbiologia, CDB, Hospital Clínic de Barcelona-IDIBAPS, Universitat de Barcelona (UB), Barcelona, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Rey-Jurado
authors.forename: Griselda
authors.initials: G
authors.lastname: Tudó
authors.forename: Sònia
authors.initials: S
authors.lastname: Borrell
authors.forename: Fernando
authors.initials: F
authors.lastname: Alcaide
authors.forename: Pere
authors.initials: P
authors.lastname: Coll
authors.forename: Montserrat
authors.initials: M
authors.lastname: Español
authors.forename: Núria
authors.initials: N
authors.lastname: Martín-Casabona
authors.forename: Virginie
authors.initials: V
authors.lastname: Mick
authors.forename: Michel
authors.initials: M
authors.lastname: Montemayor
authors.forename: Raquel
authors.initials: R
authors.lastname: Moure
authors.forename: Margarita
authors.initials: M
authors.lastname: Salvadó
authors.forename: Eva
authors.initials: E
authors.lastname: Vicente
authors.forename: Julià
authors.initials: J
authors.lastname: González-Martín
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D002374:Catalase / Q000235:genetics; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000302:isolation & purification; D010088:Oxidoreductases / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; C505805:rpoB protein, Mycobacterium tuberculosis; D010088:Oxidoreductases; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; C085257:InhA protein, Mycobacterium; D012321:DNA-Directed RNA Polymerases; D007538:Isoniazid