engleski

Interaction studies of new bioactive macrolide derivatives with bacterial ribosome

Owing to their high efficacy and safety, macrolides have been in widespread clinical use for the treatment of upper and lower respiratory tract infections. The reversible binding of macrolides to the 23S rRNA of the large ribosomal subunit, at or near the peptidyl transferase center, blocks the exiting tunnel for newly synthesized peptides and thus inhibits the synthesis of bacterial proteins. The chemical structure of clinically relevant macrolides is characterized by a macrolactone ring, usually consisting of 14–16 atoms, substituted by polar and non-polar groups and linked to one or more carbohydrate units via glycosidic bonds. Despite the fact that new antibiotics have been developed, some bacteria have acquired broad resistance, representing a global medical problem which can only be resolved by the discovery of new and more potent drugs. Our previous studies have shown that linking known macrolide antibiotics to bioactive thiosemicarbazones resulted with novel conjugates, the macrozones, efficient against multidrug resistant strains. It has also been reported that some thiosemicarbazones and their metal complexes possess anti-infective, anti-tumor and anti inflammatory activities. In this work, we studied the interactions of new bioactive macrolide conjugates and their metal complexes with the Escherichia coli ribosome by a combined use of NMR spectroscopy, fluorescence measurements and molecular modelling simulations. Saturation transfer difference (STD), WaterLogsy and transferred nuclear Overhauser effect (trNOE) NMR experiments provided valuable data about ligand conformations and binding epitopes. Fluorescence spectra were further processed by multivariate data analysis methods to assess binding constants. Molecular modelling simulations revealed the macrolide binding sites at the E. coli ribosome. The obtained results can further be exploited in the process of designing novel macrolide derivatives with activity against resistant pathogens.

macrolides, interactions, bacterial ribosome, NMR, fluorescence, molecular modelling

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