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NMR insights on the interactions of macrolides and macrozones

Macrolide antibiotics, such as azithromycin have been widely used to treat infections of both gram-positive and gram-negative bacteria [1]. They exert their biological activity by binding to bacterial ribosome at or near the peptidyl transferase center thus inhibiting protein biosynthesis. Multi-drug resistant microbial pathogens present today a serious and challenging medical problems which demands novel antimicrobial agents to be obtained. In order to overcome this issue it is necessary to elucidate and understand the drug mode of action. In order to discover and design more effective macrolide compounds, it is important to explore the interactions with ribosome and other biological targets and characterize bound conformations in solution [2–5]. We have prepared a series of bioactive azithromycin conjugates, the macrozones, by coupling thiosemicarbazones to azithromycin. Here we present results of interaction studies of macrolide antibiotics and some selected macrozones by employing a combination of NMR experiments such as transferred nuclear Overhauser effect spectroscopy (trNOESY), saturation transfer difference (STD), diffusion and solvent paramagnetic relaxation experiments and molecular modelling to characterize binding epitopes and asses bound conformations. The data so obtained can serve as a basis for the design of novel compounds with an improved biological profile

macrolide antibiotics ; resistance ; activity ; interactions ; NMR

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