Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids

• Published in: Chemistry : a European journal Vol. 21; no. 11; pp. 4350 - 4358
• Main Authors: Glanzer, Simon, Pulido, Sergio A., Tutz, Sarah, Wagner, Gabriel E., Kriechbaum, Manfred, Gubensäk, Nina, Trifunovic, Jovana, Dorn, Markus, Fabian, Walter M. F., Novak, Predrag, Reidl, Joachim, Zangger, Klaus
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 09.03.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Acids; Aggregates; Anti-Bacterial Agents - chemistry; Antibiotics; azithromycin; Bacteria; Bile; bile acids; Bile Acids and Salts - chemistry; Binding; Chemistry; Cholesterol; diffusion ordered spectroscopy (DOSY); Diseases; macrolide antibiotics; Macrolides - chemistry; Micelles; Molecular Structure; NMR spectroscopy; Solvents; Toxicity; azithromycin; NMR spectroscopy; diffusion ordered spectroscopy (DOSY); micelles; bile acids; macrolide antibiotics
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201406413

Macrolide antibiotics, such as azithromycin and erythromycin, are in widespread use for the treatment of bacterial infections. Macrolides are taken up and excreted mainly by bile. Additionally, they have been implicated in biliary system diseases and to modify the excretion of other drugs through bile. Despite mounting evidence for the interplay between macrolide antibiotics and bile acids, the molecular details of this interaction remain unknown. Herein, we show by NMR measurements that macrolides directly bind to bile acid micelles. The topology of this interaction has been determined by solvent paramagnetic relaxation enhancements (solvent PREs). The macrolides were found to be bound close to the surface of the micelle. Increasing hydrophobicity of both the macrolide and the bile acid strengthen this interaction. Both bile acid and macrolide molecules show similar solvent PREs across their whole structures, indicating that there are no preferred orientations of them in the bile micelle aggregates. The binding to bile aggregates does not impede macrolide antibiotics from targeting bacteria. In fact, the toxicity of azithromycin towards enterotoxic E. coli (ETEC) is even slightly increased in the presence of bile, as was shown by effective concentration (EC50) values. Diffusion ordered spectroscopy: It was shown that all macrolides tested bind to different bile acids with varying affinities. Strongest binding has been observed between the most hydrophobic macrolides, azithromycin and clarithromycin, to cholate and deoxycholate micelles, respectively (see scheme).