Conformational analysis of josamycin, a 16-membered macrolide free in solution and bound to bacterial ribosomes

(Note: The full text of this document is currently only available in the PDF Version )

Josyane Gharbi-Benarous, Nathalie Evrard-Todeschi, Patrick Ladam, Gildas Bertho, Marcel Delaforge and Jean-Pierre Girault


Abstract

The potent 14-membered macrolide antibiotics displayed a strong NMR response in the TRNOESY experiments whereas their metabolites which do not retain antimicrobial activity gave essentially blank TRNOESY spectra. These TRNOESY experiments are here extended to a macrolide ([hair space]josamycin) belonging to the 16-atom macrolide class in order to compare responses according to the macrocycle size. Analysis of transferred nuclear Overhauser effect (TRNOE) experiments resulted in a set of constraints for all proton pairs. These constraints were used in structure determination procedures based on molecular modelling to obtain a bound structure compatible with the experimental NMR data. This study allowed us to identify the binding structure at the ribosome for the active 16-membered macrolide. The different conformations existing in solution for this antibiotic in the free state will be compared and correlated with the binding conformation at the ribosome obtained with TRNOE experiments so as to establish a structure–activity relationship. The comparative results indicate that one conformation (called S3) pre-existing in the conformational equilibrium of macrocycle in solution and close to the major one S5, is preferred in the bound state.


References

  1. J. C. Gasc and A. Bryskier, Macrolides, ed. A. Bryskier, J. Butzler, H. Neu and P. Tulkens, Arnette Blackwell, Oxford, 1993, vol. 47, pp. 5–66 Search PubMed.
  2. H. A. Kirst and G. D. Sides, Antimicrob. Agents Chemother., 1989, 33, 1413 CAS.
  3. D. Mansuy and M. Delaforge, Macrolides, ed. A. Bryskier, J. Butzler, H. Neu and P. Tulkens, Arnette Blackwell, Oxford, 1993, pp. 635–646 Search PubMed.
  4. T. Cachet, G. Van den Mooter, R. Hauchecorne, C. Vinckier and J. Hoogmartens, Int. J. Pharm., 1989, 55, 59 CrossRef CAS.
  5. M. Skinner, R. B. Taylor and I. Kanfer, Eur. J. Pharm. Sci., 1993, 1, 61 CrossRef CAS.
  6. T. Watanabe, T. Fujii, H. Sakurai, J. Abe, K. Satake, International Symposium on the Chemistry of Natural Products, Kyoto, 1964, 146 Search PubMed.
  7. S. Omura, H. Ogura and T. Hata, Tetrahedron Lett., 1967, 1267 CrossRef CAS.
  8. M. Hiramatsu, A. Furusaki, T. Noda, K. Naya, Y. Tomiie, I. Nitta, T. Watanabe, T. Take, J. Abe, S. Omura and T. Hata, Bull. Chem. Soc. Jpn., 1970, 43, 1966 CAS.
  9. G. Bertho, P. Ladam, J. Gharbi-Benarous, M. Delaforge and J. P. Girault, J. Chim. Phys., 1998, 95, 423 CAS.
  10. G. Bertho, J. Gharbi-Benarous, P. Ladam, M. Delaforge and J. P. Girault, Bioorg. Med. Chem., 1998, 6, 209 CrossRef CAS.
  11. R. C. Goldman, S. W. Fesik and C. C. Doran, Antimicrob. Agents Chemother., 1990, 34, 426 CAS.
  12. R. Fernandez-Munoz and D. Vazquez, J. Antibiot., 1973, 26, 107 CAS.
  13. S. Pestka, Antimicrob. Agents Chemother., 1974, 6, 474 CAS.
  14. J. Barber, J. I. Gyi and D. A. Pye, J. Chem. Soc., Chem. Commun., 1991, 1249 RSC.
  15. D. A. Pye, J. I. Gyi and J. Barber, J. Chem. Soc., Chem. Commun., 1990, 1143 RSC.
  16. J. I. Gyi, R. J. Brennan, D. A. Pye and J. Barber, J. Chem. Soc., Chem. Commun., 1991, 1471 RSC.
  17. G. Dinos, D. Synetos and C. Coutsogeorgopoulos, Biochemistry, 1993, 32, 10638 CrossRef CAS.
  18. D. J. Hardy, D. M. Hensey, J. M. Beyer, C. Vojtko, E. J. McDonald and P. B. Fernandes, 1988, 32, 1710.
  19. E. Sartori, M. Delaforge and D. Mansuy, Biochem. Pharmacol., 1989, 38, 2061 CrossRef CAS.
  20. M. Delaforge and E. Sartori, Biochem. Pharmacol., 1990, 40, 223 CrossRef CAS.
  21. J. C. Gasc and A. Bryskier, Macrolides, ed. A. Bryskier, J. Butzler, H. Neu and P. Tulkens, Arnette Blackwell, Oxford, 1993, vol. 47, pp. 67–69 Search PubMed.
  22. M. Delaforge, M. Jaouen and D. Mansuy, Biochem. Pharmacol., 1983, 32, 2309 CrossRef CAS.
  23. S. Omura and M. Tishler, J. Med. Chem., 1972, 15, 1011 CrossRef CAS.
  24. C. Agouridas, P. Collette, P. Mauvais and J. F. Chantot, 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, DC, American Society for Microbiology, 1994, F-166 Search PubMed.
  25. M. R. Bendall and D. T. Pegg, J. Magn. Reson., 1983, 53, 272 CAS.
  26. A. Bax and M. F. Summers, J. Am. Chem. Soc., 1986, 108, 2093 CrossRef CAS.
  27. A. Rutar, J. Magn. Reson., 1984, 59, 306.
  28. A. Bax and R. Freeman, J. Magn. Reson., 1981, 44, 542 CAS.
  29. T. C. Wong and V. Rutar, J. Am. Chem. Soc., 1984, 106, 7380 CrossRef CAS.
  30. A. Bax, J. Magn. Reson., 1984, 57, 314 CAS.
  31. J. Gharbi-Benarous, M. Delaforge, C. K. Jankowski and J. P. Girault, J. Med. Chem., 1991, 34, 1117 CrossRef CAS.
  32. P. Ladam, J. Gharbi-Benarous, M. Piotto, M. Delaforge and J. P. Girault, Magn. Reson. Chem., 1994, 32, 1 CAS.
  33. C. A. G. Haasnoot, F. De Leeuw and C. Altona, Tetrahedron, 1980, 36, 2783 CrossRef CAS.
  34. I. Tvaroska, M. Hricovini and E. Petrakova, Carbohydr. Res., 1989, 189, 359 CrossRef CAS.
  35. J. R. Everett, I. K. Hatton and J. W. Tyler, Magn. Reson. Chem., 1990, 28, 114 CAS.
  36. J. Gharbi-Benarous, P. Ladam, M. Delaforge and J. P. Girault, J. Chem. Soc., Perkin Trans. 2, 1993, 2303 RSC.
  37. P. Dauber-Osguthorpe, V. A. Roberts, D. J. Osguthorpe, J. Wolff, M. Genest and A. T. Hagler, Proteins: Struct., Funct. Genet., 1988, 4, 31 CAS.
  38. S. J. Weiner, P. Kollmann, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, S. Profeta and P. Weiner, J. Am. Chem. Soc., 1984, 106, 765 CrossRef CAS.
  39. N. R. Nirmala, G. M. Lippens and K. Hallenga, J. Magn. Reson., 1992, 100, 25 CAS.
  40. P. Alam, J. Barber, R. J. Brennan, K. Kennedy and M. H. H. Tehrani, Magn. Reson. Chem., 1995, 33, 228 CAS.
  41. G. Bertho, P. Ladam, J. Gharbi-Benarous, M. Delaforge and J. P. Girault, Int. J. Biol. Macromol., 1998, 22, 103 CrossRef CAS.
  42. K. Osono, K. Moriyama and M. Murakami, J. Antibiot., 1974, 27, 366.
  43. T. R. Tritton, Biochemistry, 1977, 16, 4133 CrossRef CAS.
  44. A. Awan, R. J. Brennan, A. C. Regan and J. Barber, J. Chem. Soc., Chem. Commun., 1995, 16, 1653 RSC.
  45. H. E. Homann and K. H. Nierhaus, Eur. J. Biochem., 1971, 20, 249 CAS.
  46. D. Vazquez, Inhibitors of Protein Synthesis, Springer Verlag, Berlin, 1979 Search PubMed.
  47. D. Moazed and H. F. Noller, Biochimie, 1987, 69, 879 CrossRef CAS.
  48. A. Contreras and D. Vazquez, Eur. J. Biochem., 1977, 74, 539 CAS.
  49. O. Bischof, H. Urlaub, V. Kruft and B. Wittmann-Liebold, J. Biol. Chem., 1995, 270, 23060 CrossRef CAS.
  50. U. Dinur and A. T. Hagler, J. Chem. Phys., 1989, 91, 2949 CrossRef CAS.
  51. H. J. C. Berendsen, J. P. M. Postma, W. F. v. Gunsteren, A. DiNola and J. R. Haak, J. Chem. Phys., 1984, 81, 3684 CrossRef CAS.
Click here to see how this site uses Cookies. View our privacy policy here.