title: Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue.
abstract: The diarylquinoline TMC207 kills Mycobacterium tuberculosis by specifically inhibiting ATP synthase. We show here that human mitochondrial ATP synthase (50% inhibitory concentration [IC(50)] of >200 microM) displayed more than 20,000-fold lower sensitivity for TMC207 compared to that of mycobacterial ATP synthase (IC(50) of 10 nM). Also, oxygen consumption in mouse liver and bovine heart mitochondria showed very low sensitivity for TMC207. These results suggest that TMC207 may not elicit ATP synthesis-related toxicity in mammalian cells. ATP synthase, although highly conserved between prokaryotes and eukaryotes, may still qualify as an attractive antibiotic target.
authors.affiliation: Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Haagsma
authors.forename: Rooda
authors.initials: R
authors.lastname: Abdillahi-Ibrahim
authors.forename: Marijke J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Klaas
authors.initials: K
authors.lastname: Krab
authors.forename: Karen
authors.initials: K
authors.lastname: Vergauwen
authors.forename: Jerome
authors.initials: J
authors.lastname: Guillemont
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Holger
authors.initials: H
authors.lastname: Lill
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.forename: Dirk
authors.initials: D
authors.lastname: Bald
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D064687:Diarylquinolines; D004305:Dose-Response Relationship, Drug; D005057:Eukaryotic Cells / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D012680:Sensitivity and Specificity
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline; D025261:Mitochondrial Proton-Translocating ATPases