Diarylquinolines target subunit c of mycobacterial ATP synthase.
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.
Koul
Anil
A
Department of Antimicrobial Research, Tibotec BVBA, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium. akoul@prdbe.jnj.com
Dendouga
Najoua
N
Vergauwen
Karen
K
Molenberghs
Brenda
B
Vranckx
Luc
L
Willebrords
Rudy
R
Ristic
Zorica
Z
Lill
Holger
H
Dorange
Ismet
I
Guillemont
Jerome
J
Bald
Dirk
D
Andries
Koen
K
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*
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