title: Diarylquinolines target subunit c of mycobacterial ATP synthase.
abstract: The diarylquinoline R207910 (TMC207) is a promising candidate in clinical development for the treatment of tuberculosis. Though R207910-resistant mycobacteria bear mutations in ATP synthase, the compound's precise target is not known. Here we establish by genetic, biochemical and binding assays that the oligomeric subunit c (AtpE) of ATP synthase is the target of R207910. Thus targeting energy metabolism is a new, promising approach for antibacterial drug discovery.
authors.affiliation: Department of Antimicrobial Research, Tibotec BVBA, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium. akoul@prdbe.jnj.com
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.forename: Najoua
authors.initials: N
authors.lastname: Dendouga
authors.forename: Karen
authors.initials: K
authors.lastname: Vergauwen
authors.forename: Brenda
authors.initials: B
authors.lastname: Molenberghs
authors.forename: Luc
authors.initials: L
authors.lastname: Vranckx
authors.forename: Rudy
authors.initials: R
authors.lastname: Willebrords
authors.forename: Zorica
authors.initials: Z
authors.lastname: Ristic
authors.forename: Holger
authors.initials: H
authors.lastname: Lill
authors.forename: Ismet
authors.initials: I
authors.lastname: Dorange
authors.forename: Jerome
authors.initials: J
authors.lastname: Guillemont
authors.forename: Dirk
authors.initials: D
authors.lastname: Bald
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
mesh_terms: D025181:ATP Synthetase Complexes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D025243:Bacterial Proton-Translocating ATPases; D001665:Binding Sites; D064687:Diarylquinolines; D015180:Electrophoresis, Gel, Two-Dimensional; D007700:Kinetics; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology; D021122:Protein Subunits / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D064687:Diarylquinolines; D021122:Protein Subunits; D011804:Quinolines; C493870:bedaquiline; D025181:ATP Synthetase Complexes; C521357:ATP synthase subunit C, Mycobacterium tuberculosis; D025243:Bacterial Proton-Translocating ATPases