title: iniBAC induction Is Vitamin B12- and MutAB-dependent in Mycobacterium marinum.
abstract: Tuberculosis can be treated with a 6-month regimen of antibiotics. Although the targets of most of the first-line antibiotics have been identified, less research has focused on the intrabacterial stress responses that follow upon treatment with antibiotics. Studying the roles of these stress genes may lead to the identification of crucial stress-coping mechanisms that can provide additional drug targets to increase treatment efficacy. A three-gene operon with unknown function that is strongly up-regulated upon treatment with isoniazid and ethambutol is the iniBAC operon. We have reproduced these findings and show that iniBAC genes are also induced in infected host cells, although with higher variability. Next, we set out to elucidate the genetic network that results in iniBAC induction in Mycobacterium marinum By transposon mutagenesis, we identified that the operon is highly induced by mutations in genes encoding enzymes of the vitamin B12 biosynthesis pathway and the vitamin B12-dependent methylmalonyl-CoA-mutase MutAB. Lipid analysis showed that a mutA::tn mutant has decreased phthiocerol dimycocerosates levels, suggesting a link between iniBAC induction and the production of methyl-branched lipids. Moreover, a similar screen in Mycobacterium bovis BCG identified that phthiocerol dimycocerosate biosynthesis mutants cause the up-regulation of iniBAC genes. Based on these data, we propose that iniBAC is induced in response to mutations that cause defects in the biosynthesis of methyl-branched lipids. The resulting metabolic stress caused by these mutations or caused by ethambutol or isoniazid treatment may be relieved by iniBAC to increase the chance of bacterial survival.
authors.affiliation: From the Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Boot
authors.affiliation: From the Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Sparrius
authors.affiliation: From the Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Kin Ki
authors.initials: KK
authors.lastname: Jim
authors.affiliation: From the Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Susanna
authors.initials: S
authors.lastname: Commandeur
authors.affiliation: From the Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Speer
authors.affiliation: From the Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: van de Weerd
authors.affiliation: From the Department of Medical Microbiology and Infection Control, VU University Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands w.bitter@vumc.nl.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bitter
mesh_terms: D001430:Bacteriocins / Q000235:genetics / Q000378:metabolism*; D004977:Ethambutol / Q000494:pharmacology; D007538:Isoniazid / Q000494:pharmacology; D008563:Membrane Lipids / Q000096:biosynthesis / Q000235:genetics; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics; D009163:Mycobacterium bovis / Q000235:genetics / Q000378:metabolism; D019910:Mycobacterium marinum / Q000235:genetics / Q000378:metabolism*; D009876:Operon / Q000502:physiology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D014805:Vitamin B 12 / Q000494:pharmacology*
chemical_list: D001430:Bacteriocins; D008563:Membrane Lipids; D010455:Peptides; C110490:mutacin II prepeptide, bacteria; D004977:Ethambutol; D014805:Vitamin B 12; D007538:Isoniazid
keywords: antibiotics; gene regulation; iniBAC; mutAB; mycobacteria; stress response; tuberculosis; vitamin B12