title: Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis.
abstract: The emergence of multi- and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) has intensified the critical public health implications of this global disease. The fitness of Mycobacterium tuberculosis (M.tb.) strains exhibiting MDR and XDR phenotypes is of fundamental importance in predicting whether the MDR-/XDR-TB epidemic will be sustained across the human population. Here we describe a potential mechanism of M.tb. resistance to the TB drug isoniazid (INH) conferred by loss of a sigma factor, SigI. We demonstrate that the gain of INH resistance in the M.tb. ΔsigI mutant might not diminish the organism's fitness for causing disease. These findings have significant implications when considering the ability of drug-resistant M.tb. strains to initiate untreatable TB epidemics, as it is possible that loss or alteration of SigI function could have a role in the generation of MDR and XDR M.tb. strains of suitable fitness to spread in a community setting.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.forename: Scott
authors.initials: S
authors.lastname: Nolan
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Geiman
authors.forename: Shichun
authors.initials: S
authors.lastname: Lun
authors.forename: Haidan
authors.initials: H
authors.lastname: Guo
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial; D005798:Genes, Bacterial; D005809:Genes, Regulator; D007538:Isoniazid / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D018085:Regulon; D012808:Sigma Factor / Q000235:genetics*; D014158:Transcription, Genetic; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D012808:Sigma Factor; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; D007538:Isoniazid