title: Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis.
abstract: We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc1 complex and the risk of targeting energy metabolism with new drugs.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kriti
authors.initials: K
authors.lastname: Arora
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Ochoa-Montaño
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Tsang
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.affiliation: School of Pathology, University of the Witwatersrand, Parktown, Johannesburg, South Africa.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Dawes
authors.affiliation: School of Pathology, University of the Witwatersrand, Parktown, Johannesburg, South Africa MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.
authors.forename: Valerie
authors.initials: V
authors.lastname: Mizrahi
authors.affiliation: Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, United Kingdom.
authors.forename: Tracy
authors.initials: T
authors.lastname: Bayliss
authors.affiliation: Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, United Kingdom.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Mackenzie
authors.affiliation: Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, United Kingdom.
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.affiliation: Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, United Kingdom.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Ray
authors.affiliation: Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Uh
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA hboshoff@niaid.nih.gov.
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001665:Binding Sites; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects; D055786:Gene Knockout Techniques; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D010078:Oxazines / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy*; D014966:Xanthenes / Q000737:chemistry
chemical_list: D000995:Antitubercular Agents; D010078:Oxazines; D011725:Pyridines; D014966:Xanthenes; C005843:resazurin; D003576:Electron Transport Complex IV; C001439:imidazo(1,2-a)pyridine