title: The cytochrome bd-type quinol oxidase is important for survival of Mycobacterium smegmatis under peroxide and antibiotic-induced stress.
abstract: Targeting respiration and ATP synthesis has received strong interest as a new strategy for combatting drug-resistant Mycobacterium tuberculosis. Mycobacteria employ a respiratory chain terminating with two branches. One of the branches includes a cytochrome bc1 complex and an aa3-type cytochrome c oxidase while the other branch terminates with a cytochrome bd-type quinol oxidase. In this communication we show that genetic inactivation of cytochrome bd, but not of cytochrome bc1, enhances the susceptibility of Mycobacterium smegmatis to hydrogen peroxide and antibiotic-induced stress. The type-II NADH dehydrogenase effector clofazimine and the ATP synthase inhibitor bedaquiline were bacteriostatic against wild-type M. smegmatis, but strongly bactericidal against a cytochrome bd mutant. We also demonstrated that the quinone-analog aurachin D inhibited mycobacterial cytochrome bd at sub-micromolar concentrations. Our results identify cytochrome bd as a key survival factor in M. smegmatis during antibiotic stress. Targeting the cytochrome bd respiratory branch therefore appears to be a promising strategy that may enhance the bactericidal activity of existing tuberculosis drugs.
authors.affiliation: Department of Molecular Cell Biology, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Earth- and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Molecular Cell Biology, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Earth- and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Marieke H
authors.initials: MH
authors.lastname: Heineke
authors.affiliation: Infectious diseases and vaccines therapeutic area, Janssen Research &Development, Johnson &Johnson Pharmaceuticals, Turnhoutseweg 30, 2340-Beerse, Belgium.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.affiliation: Infectious diseases and vaccines therapeutic area, Janssen Research &Development, Johnson &Johnson Pharmaceuticals, Turnhoutseweg 30, 2340-Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.affiliation: Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cook
authors.affiliation: Department of Molecular Cell Biology, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Earth- and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Holger
authors.initials: H
authors.lastname: Lill
authors.affiliation: Department of Molecular Cell Biology, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Earth- and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: van Spanning
authors.affiliation: Department of Molecular Cell Biology, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Earth- and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bald
mesh_terms: D025181:ATP Synthetase Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002991:Clofazimine / Q000494:pharmacology; D064687:Diarylquinolines / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006861:Hydrogen Peroxide / Q000633:toxicity*; D009154:Mutation; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D064687:Diarylquinolines; D015363:Quinolones; D017382:Reactive Oxygen Species; C052097:aurachin D; C493870:bedaquiline; D006861:Hydrogen Peroxide; D002991:Clofazimine; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D025181:ATP Synthetase Complexes