Lincomycin and clindamycin conformations. A fragment shared by macrolides,ketolides and lincosamides determined from TRNOE ribosome-bound conformations

Two important lincosamide antibiotics, lincomycin and clindamycin were stud ied in the complex state with the bacterial ribosome after a conformational analysis by H-1 and C-13 NMR spectroscopy and molecular modelling of the u nbound molecules. Lincosamide-ribosome interactions were investigated using two-dimensional transferred nuclear Overhauser effect spectroscopy (TRNOES Y), resulting in a bound structure compatible with the experimental NMR dat a. The results compared with the conformational analysis of the substrates in solution indicate that specific conformations are preferred in the bound state. Clindamycin, the more bioactive antibiotic studied, displayed a str onger NMR response than lincomycin showing that in lincosamide-ribosome int eractions, a low affinity binding level is associated to the tight binding one and is related to biological activity. This study shows that conformati on plays an essential role for the low affinity binding site. Superimpositi on of lincosamide, macrolide and ketolide bound structures exhibited confor mational similarities in a particular fragment which is in agreement with a hypothesis of partial overlapping lincosamide and macrolide binding sites. (C) 2000 Elsevier Science Ltd. All rights reserved.