Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: ATP synthase subunit composition and inhibition by R207910.
Figure 2: Binding studies using compound-linked affinity chromatography and BIAcore.


  1. 1

    Dye, C., Scheele, S., Dolin, P., Pathania, V. & Raviglione, M.C. J. Am. Med. Assoc. 282, 677–686 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Andries, K. et al. Science 307, 223–227 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Ji, B. et al. Antimicrob. Agents Chemother. 50, 1921–1926 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Junge, W. & Nelson, N. Science 308, 642–644 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Walsh, C. Nature 406, 775–781 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Telenti, A. et al. J. Clin. Microbiol. 35, 719–723 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    de Jonge, M.R., Koymans, L.H., Guillemont, J.E., Koul, A. & Andries, K. Proteins published online 23 March 2007 (doi:10.1002/prot.21376).

    CAS  Article  Google Scholar 

  8. 8

    Telenti, A. et al. Nat. Med. 3, 567–570 (1997).

    CAS  Article  Google Scholar 

  9. 9

    Wang, R., Prince, J.T. & Marcotte, E.M. Genome Res. 15, 1118–1126 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Tran, S.L. & Cook, G.M. J. Bacteriol. 187, 5023–5028 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Ferrandiz, M.J. & de la Campa, A.G. FEMS Microbiol. Lett. 212, 133–138 (2002).

    CAS  Article  Google Scholar 

Download references


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).

Author information




A.K. wrote the manuscript as a project team leader, with contributions from K.A., D.B. and N.D. A.K., K.A., N.D. and D.B. contributed to study design and data analysis. K.V. did ATP synthesis assay; N.D. made constructs for subunit c purification; N.D. and B.M. did affinity chromatography assays and complementation studies; R.W. contributed to DARQ screening; L.V. did ATP measurements, MIC determinations and isolation of resistant mutants; J.G. and I.D. synthesized DARQs, separated isomers and performed chemical characterizations; and H.L. and Z.R. contributed to the BIAcore binding experiments.

Corresponding author

Correspondence to Anil Koul.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary Fig. 1

Chemical structure of R207910 (R,S) and related isomers. (PDF 19 kb)

Supplementary Fig. 2

Genetic organization of mycobacterial ATP synthase and homology model of subunit-c. (PDF 96 kb)

Supplementary Fig. 3

Characterization of R207910-resistant M. tuberculosis strains. (PDF 27 kb)

Supplementary Fig. 4

Binding studies using affinity capture chromatography. (PDF 76 kb)

Supplementary Fig. 5

BIAcore interaction analysis of purified whole ATP synthase from Bacillus PS3 or its α3β3γ sub-complex with R207910. (PDF 46 kb)

Supplementary Table 1

MICs of R207910 stereoisomers in different mycobacterial species. (PDF 44 kb)

Supplementary Table 2

Inhibition of M. smegmatis ATP synthase activity by DARQ compounds. (PDF 18 kb)

Supplementary Methods (PDF 158 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Koul, A., Dendouga, N., Vergauwen, K. et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol 3, 323–324 (2007).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing