Investigation of the Binding of the Macrolide Antibiotic Telithromycin to Human Serum Albumin by NMR Spectroscopy.

The macrolide antibiotic telithromycin was developed to avoid common antibiotic resistances, yet it has been recently withdrawn from the European market due to severe side effects. Both side effects and the effectiveness of a drug can be related to the strength of its interaction with human serum albumin (HSA). However, as of yet, interactions between telithromycin and HSA have not been thoroughly studied. In this work, we evaluate the interaction strength and structural details of telithromycin and HSA via diffusion ordered spectroscopy (DOSY) and transferred NOE measurements. The binding strengths are compared with those of related macrolides. Our results show that the interaction strength increases with the decreasing polarity of the side chains in the antibiotic. Among the tested macrolide antibiotics, telithromycin interacted the strongest with HSA. Structure calculations based on transferred NOEs, using DFT calculations, show that telithromycin adopts a specific conformation upon binding, which shields the polar moieties attached to the aglycon and enables more hydrophobic interactions with HSA.