Cinnamide Derivatives of d-Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa.
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.
Chemical Biology of Carbohydrates Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Universitätsstrasse 1066123 Saarbrücken Germany; Department of Chemistry and Graduate School Chemical Biology University of Konstanz 78457 KonstanzGermany; Deutsches Zentrum für Infektionsforschung (DZIF) Inhoffenstraße 738124 Braunschweig Germany.
Roman
R
Sommer
Chemical Biology of Carbohydrates Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Universitätsstrasse 1066123 Saarbrücken Germany; Department of Chemistry and Graduate School Chemical Biology University of Konstanz 78457 KonstanzGermany; Deutsches Zentrum für Infektionsforschung (DZIF) Inhoffenstraße 738124 Braunschweig Germany.
Dirk
D
Hauck
Centre de Recherche sur les Macromolécules Végétales (CERMAV-UPR5301) CNRS and Université Grenoble Alpes, BP53 38041 Grenoble cedex 9 France.
Annabelle
A
Varrot
Chemical Biology of Carbohydrates Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Universitätsstrasse 1066123 Saarbrücken Germany; Deutsches Zentrum für Infektionsforschung (DZIF) Inhoffenstraße 738124 Braunschweig Germany.
Stefanie
S
Wagner
Centre de Recherche sur les Macromolécules Végétales (CERMAV-UPR5301) CNRS and Université Grenoble Alpes, BP53 38041 Grenoble cedex 9 France.
Aymeric
A
Audfray
Department of Chemistry and Graduate School Chemical Biology University of Konstanz 78457 Konstanz Germany; Institute of Chemistry University of Potsdam 14476 Potsdam Germany.
Andreas
A
Prestel
Department of Chemistry and Graduate School Chemical Biology University of Konstanz 78457 Konstanz Germany; Institute of Chemistry University of Potsdam 14476 Potsdam Germany.
Heiko M
HM
Möller
Centre de Recherche sur les Macromolécules Végétales (CERMAV-UPR5301) CNRS and Université Grenoble Alpes, BP53 38041 Grenoble cedex 9 France.
Anne
A
Imberty
Chemical Biology of Carbohydrates Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Universitätsstrasse 1066123 Saarbrücken Germany; Department of Chemistry and Graduate School Chemical Biology University of Konstanz 78457 KonstanzGermany; Deutsches Zentrum für Infektionsforschung (DZIF) Inhoffenstraße 738124 Braunschweig Germany.
Alexander
A
Titz
LecB/PA-IIL; carbohydrates; glycoconjugates; glycomimetics; lectins