Conformations in solution and bound to bacterial ribosomes of ketolides, HMR 3647 (telithromycin) and RU 72366: A new class of highly potent antibacterials

The new class of antibiotics called ketolides is endowed with remarkable an tibacterial activity against macrolide-resistant strains. Further modificat ions of the 3 keto-macrolactone backbone led to 11,12-hydrazonocarbamate ke tolides with an imidazolyl-pyridine chain: the file-leader of ketolide clas s, HMR 3647 (telithromycin), and its N-bis-demethyl-derivative, RU 72366. T he potency of HMR 3647 is higher than that of RU 72366. Stereospecific H-1 and C-13 resonance assignments of HMR 3647 and RU 72366 have been determine d and have allowed a detailed quantitative conformational analysis of the u ncomplexed form of the molecules. The comparative conformation of HMR 3647 in solution and its N-bis-demethyl-derivative in D2O has been carried out u sing different heteronuclear correlation experiments in, conjunction with n uclear Overhauser effect experiments and in particular long-range (3)J(CH) coupling constants and using molecular dynamics (MD) methods. The study of ketolide-ribosome interaction has been investigated using two-dimensional t ransferred nuclear Overhauser effect spectroscopy (TRNOESY). The database o f ribosome-bound ketolide structures has been used to compare the structure (s) of ketolide in ribosome-ketolide complexes with the conformational pref erences of free ketolides and to highlight the significant differences betw een HMR 3647 and RU 72366. A comparison of the conformations bound to ribos ome was made with those of other previously studied ketolide (RU 004) and m acrolides and would explain the remarkable potencies of HMR 3647 in inhibit ing protein synthesis. (C) 2000 Elsevier Science Ltd. All rights reserved.