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Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA


Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor– and lipid substrate–binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new pyridomycin derivatives.

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Figure 1: Mechanism of action of pyridomycin.
Figure 2: Architecture of the pyridomycin-binding site and critical contacts.
Figure 3: Comparison of the binding pockets of various InhA inhibitors.

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  1. Glaziou, P., Floyd, K. & Raviglione, M. Clin. Chest Med. 30, 621–636 (2009).

    Article  Google Scholar 

  2. Cegielski, J.P. Clin. Infect. Dis. 50, S195–S200 (2010).

    Article  Google Scholar 

  3. Sullivan, T.J. et al. ACS Chem. Biol. 1, 43–53 (2006).

    Article  CAS  Google Scholar 

  4. He, X., Alian, A., Stroud, R. & Ortiz de Montellano, P.R. J. Med. Chem. 49, 6308–6323 (2006).

    Article  CAS  Google Scholar 

  5. Ballell Pages, L. et al. (Pyrazol-3-yl)-1,3,4-thiadiazole-2-amine and (pyrazol-3-yl)-1,3,4-thiazole-2-amine compounds. World Intellectual Property Organization WO2010118852 A1 (2010).

  6. Shirude, P.S. et al. J. Med. Chem. 10.1021/jm401382v (11 November 2013).

  7. Hartkoorn, R.C. et al. EMBO Mol. Med. 4, 1032–1042 (2012).

    Article  CAS  Google Scholar 

  8. Koyama, G., Iitaka, Y., Maeda, K. & Umezawa, H. Tetrahedr. Lett. 37, 3587–3590 (1967).

    Article  CAS  Google Scholar 

  9. Rozwarski, D.A., Vilcheze, C., Sugantino, M., Bittman, R. & Sacchettini, J.C. J. Biol. Chem. 274, 15582–15589 (1999).

    Article  CAS  Google Scholar 

  10. Horlacher, O.P., Hartkoorn, R.C., Cole, S.T. & Altmann, K.-H. ACS Med. Chem. Lett. 4, 264–268 (2013).

    Article  CAS  Google Scholar 

  11. McMurry, L.M., Oethinger, M. & Levy, S.B. Nature 394, 531–532 (1998).

    Article  CAS  Google Scholar 

  12. Heath, R.J., Yu, Y.T., Shapiro, M.A., Olson, E. & Rock, C.O. J. Biol. Chem. 273, 30316–30320 (1998).

    Article  CAS  Google Scholar 

  13. Freundlich, J.S. et al. ChemMedChem 4, 241–248 (2009).

    Article  CAS  Google Scholar 

  14. He, X., Alian, A. & Ortiz de Montellano, P.R. Bioorg. Med. Chem. 15, 6649–6658 (2007).

    Article  CAS  Google Scholar 

  15. Pan, P. & Tonge, P.J. Curr. Top. Med. Chem. 12, 672–693 (2012).

    Article  CAS  Google Scholar 

  16. Jörnvall, H. et al. Biochemistry 34, 6003–6013 (1995).

    Article  Google Scholar 

  17. Persson, B. & Kallberg, Y. Chem. Biol. Interact. 202, 111–115 (2013).

    Article  CAS  Google Scholar 

  18. Dutta, D., Bhattacharyya, S., Roychowdhury, A., Biswas, R. & Das, A.K. Biochem. J. 450, 127–139 (2013).

    Article  CAS  Google Scholar 

  19. Ward, R.A. et al. J. Med. Chem. 55, 3285–3306 (2012).

    Article  CAS  Google Scholar 

  20. Cameron, A. et al. J. Biol. Chem. 279, 31429–31439 (2004).

    Article  CAS  Google Scholar 

  21. Maeda, K., Kosaka, H., Okami, Y. & Umezawa, H. J. Antibiot. (Tokyo) 6, 140 (1953).

    CAS  Google Scholar 

  22. Kuo, M.R. et al. J. Biol. Chem. 278, 20851–20859 (2003).

    Article  CAS  Google Scholar 

  23. Luckner, S.R., Liu, N., am Ende, C.W., Tonge, P.J. & Kisker, C. J. Biol. Chem. 285, 14330–14337 (2010).

    Article  CAS  Google Scholar 

  24. Dias, M.V. et al. J. Struct. Biol. 159, 369–380 (2007).

    Article  CAS  Google Scholar 

  25. Winn, M.D. et al. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011).

    Article  CAS  Google Scholar 

  26. Smart, O.S. et al. Grade version 1.1.1 (Cambridge, United Kingdom, Global Phasing Ltd.) (2011).

  27. Bruno, I.J. et al. J. Chem. Inf. Comput. Sci. 44, 2133–2144 (2004).

    Article  CAS  Google Scholar 

  28. Murshudov, G.N., Vagin, A.A. & Dodson, E.J. Acta Crystallogr. D Biol. Crystallogr. 53, 240–255 (1997).

    Article  CAS  Google Scholar 

  29. Bricogne, G.B.E. et al. BUSTER version 2.11.2 (Cambridge, United Kingdom: Global Phasing Ltd.) (2011).

  30. Kabsch, W. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 (2010).

    Article  CAS  Google Scholar 

  31. McCoy, A.J. et al. J. Appl. Crystallogr. 40, 658–674 (2007).

    Article  CAS  Google Scholar 

  32. Schüttelkopf, A.W. & van Aalten, D.M. Acta Crystallogr. D Biol. Crystallogr. 60, 1355–1363 (2004).

    Article  Google Scholar 

  33. Laskowski, R.A., Rullmannn, J.A., MacArthur, M.W., Kaptein, R. & Thornton, J.M. J. Biomol. NMR 8, 477–486 (1996).

    Article  CAS  Google Scholar 

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The authors would like to thank S. Surade (University of Cambridge) for providing the InhA expression plasmid (pIH51), S. Boy-Röttger and G. Cuanoud (both from EPFL) for technical assistance and G. Shiek (AstraZeneca) for protein supply. The research leading to these results received funding from the European Community's Seventh Framework Programme (grant 260872). J. Neres is the recipient of a Marie Curie fellowship from the European Commission.

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Authors and Affiliations



R.C.H., F.P., J.A.R., H.G., J.N. and O.P.H. designed the experiments. R.C.H., F.P., J.A.R., H.G. and J.N. performed the experiments. R.C.H., F.P., J.A.R. and J.N. analyzed data. K.-H.A. and O.P.H. contributed reagents. R.C.H., F.P., J.A.R., J.N. and S.T.C. wrote the paper.

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Correspondence to Stewart T Cole.

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R.C.H., O.P.H., K.-H.A. and S.T.C. are named inventors on patents relating to this work.

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Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–3. (PDF 1091 kb)

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Hartkoorn, R., Pojer, F., Read, J. et al. Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA. Nat Chem Biol 10, 96–98 (2014).

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