title: Rifampicin-induced transcriptome response in rifampicin-resistant Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) is still a major life-threatening infectious disease, within which especially the rise of multidrug resistant TB (MDR-TB) is currently worrying. This study focuses on mechanisms of development of rifampicin resistance, since rifampicin seems to play an important role in the development of MDR-TB. To provide further insight in rifampicin resistance, we performed a genome-wide transcriptional profile analysis for Mycobacterium tuberculosis (M. tuberculosis) using microarray technology and qRT-PCR analysis. We exposed a rifampicin-susceptible H37Rv wild type (H37Rv-WT) and a rifampicin-resistant progeny H37Rv strain with a H526Y mutation in the rpoB gene (H37Rv-H526Y) to several concentrations of rifampicin, to define the effect of rifampicin on the transcription profile. Our study showed that there are resistance-dependant differences in response between both M. tuberculosis strains. Gene clusters associated with efflux, transport and virulence were altered in the rifampicin-resistant H37Rv mutant compared to the rifampicin-susceptible H37Rv-WT strain after exposure to rifampicin. We conclude that the small gene cluster Rv0559c-Rv0560c in the H37Rv-H526Y strain was remarkably up-regulated in the microarray analysis and qRT-PCR results and appeared to be dependent on rifampicin concentration and time of exposure. Therefore this study suggests that Rv0559c and Rv0560c play a pivotal role in rifampicin resistance of M. tuberculosis. Further investigation of Rv0559c and Rv0560c is needed to reveal function and mechanism of both genes that were triggered upon rifampicin exposure.
authors.affiliation: Erasmus MC, University Medical Centre Rotterdam, Department of Medical Microbiology & Infectious Diseases, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. g.deknegt@erasmusmc.nl
authors.forename: Gerjo J
authors.initials: GJ
authors.lastname: de Knegt
authors.forename: Oskar
authors.initials: O
authors.lastname: Bruning
authors.forename: Marian T
authors.initials: MT
authors.lastname: ten Kate
authors.forename: Mark
authors.initials: M
authors.lastname: de Jong
authors.forename: Alex
authors.initials: A
authors.lastname: van Belkum
authors.forename: Hubert P
authors.initials: HP
authors.lastname: Endtz
authors.forename: Timo M
authors.initials: TM
authors.lastname: Breit
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
authors.forename: Jurriaan E M
authors.initials: JE
authors.lastname: de Steenwinkel
mesh_terms: D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial; D055106:Genome-Wide Association Study; D006801:Humans; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012293:Rifampin / Q000494:pharmacology*; D059467:Transcriptome / Q000235:genetics*; D014774:Virulence / Q000235:genetics
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin