Cinnamide Derivatives of d‐Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa

ChemistryOpen

Roman Sommer³  Dirk Hauck³  Dr. Annabelle Varrot¹  Dr. Stefanie Wagner³  Dr. Aymeric Audfray¹  Andreas Prestel²  Prof. Heiko M. Möller²  Dr. Anne Imberty¹ 

[1] Centre de Recherche sur les Macromolécules Végétales (CERMAV-UPR5301), CNRS and Université Grenoble Alpes, BP53, Grenoble cedex 9, France;Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, Konstanz, Germany;Chemical Biology of Carbohydrates, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany

关键词: carbohydrates;    glycoconjugates;    glycomimetics;    LecB/PA-IIL;    lectins;   

DOI  :  10.1002/open.201500162

来源: Wiley

【 摘 要 】

Abstract

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen with high antibiotic resistance. Its lectin LecB was identified as a virulence factor and is relevant in bacterial adhesion and biofilm formation. Inhibition of LecB with carbohydrate-based ligands results in a decrease in toxicity and biofilm formation. We recently discovered two classes of potent drug-like glycomimetic inhibitors, that is, sulfonamides and cinnamides of d-mannose. Here, we describe the chemical synthesis and biochemical evaluation of more than 20 derivatives with increased potency compared to the unsubstituted cinnamide. The structure–activity relationship (SAR) obtained and the extended biophysical characterization allowed the experimental determination of the binding mode of these cinnamides with LecB. The established surface binding mode now allows future rational structure-based drug design. Importantly, all glycomimetics tested showed extended receptor residence times with half-lives in the 5–20 min range, a prerequisite for therapeutic application. Thus, the glycomimetics described here provide an excellent basis for future development of anti-infectives against this multidrug-resistant pathogen.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

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