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.
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We thank P. Janssens, T. Gevers, H. Szel, J. Hendrickx, A. Shanmugham, E. Pasquier, A. Poncelet, P. Palandjian, S. Masure, W. Bruinzeel and P. Verhasselt for technical help; N. Lounis, L. Geeraert and M. Haxaire-Theeuwes for critical reading; E. Mortz (Alphalyse, Denmark) for mass spectrometry analysis; H. Van Vlijmen for R207910-docking figure; L. Leijssen for help with figures; and Vichem (Budapest) for coupling experiments. Z.R., H.L. and D.B. acknowledge EU financial support (Marie-Curie MRTN-CT-2005-019481).
Research for this project is mainly provided by Johnson & Johnson Pharmaceuticals. A.K., N.D., K.V., B.M., L.V., R.W., I.D., J.G and K.A. are employees of Johnson & Johnson.
Chemical structure of R207910 (R,S) and related isomers. (PDF 19 kb)
Genetic organization of mycobacterial ATP synthase and homology model of subunit-c. (PDF 96 kb)
Characterization of R207910-resistant M. tuberculosis strains. (PDF 27 kb)
Binding studies using affinity capture chromatography. (PDF 76 kb)
BIAcore interaction analysis of purified whole ATP synthase from Bacillus PS3 or its α3β3γ sub-complex with R207910. (PDF 46 kb)
MICs of R207910 stereoisomers in different mycobacterial species. (PDF 44 kb)
Inhibition of M. smegmatis ATP synthase activity by DARQ compounds. (PDF 18 kb)
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Koul, A., Dendouga, N., Vergauwen, K. et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol 3, 323–324 (2007). https://doi.org/10.1038/nchembio884
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