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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.

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

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Acknowledgements

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

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Authors

Contributions

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.

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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)

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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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