Systematic Approach to Understanding Macrolide−Ribosome Interactions:  NMR and Modeling Studies of Oleandomycin and Its Derivatives

Abstract

The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10,11-anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved biological profile.

Antimicrobial Susceptibility Testing, Drug Resistance Mechanisms, and Therapy of Infections with Nontuberculous Mycobacteria

“…The macrolides and the keto derivatives, the ketolides, act by binding in the peptide exit tunnel of the ribosome (125,147,273,341) and thus preventing the growing peptide chain from vacating the peptidyltransferase center of the ribosome. This is believed to "gum up" the ribosome and prevent the further elongation of the nascent peptide chain.…”

NMR Spectroscopy for Studying Interactions of Bioactive Molecules

“…Novak et al [146][147][148][149][150] have shown that a systematic approach combining NMR and molecular modelling calculations could be applicable to conformational studies of free and bound macrolides and their interactions with ribosomes. Their results [146][147][148][149][150], and those of other groups [151][152][153][154][155], have shown that macrolides adopt two major conformational families, folded-out and folded-in, referring to the outward and inward folding of the ring fragment 3C-5C ( Figure 5.10).…”

Electrochemical Synthesis, Structure Elucidation and Antibacterial Evaluation of 9a-aza-9a-chloro-9a-homoerythromycin A

“…Conformational studies on macrolides [12][13][14] have shown the existence of two major conformational families: folded-out and folded-in, referring to the outward and inward folding of the macrocycle ring fragment C3-C5. Those studies demonstrated that vicinal coupling constants 3 J H2H3 and NOE proton-proton contacts H4-H11 and H3-H11, respectively, can serve as good indicators of the ring folding.…”