Publikationen (FIS)

Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa

verfasst von
Roman Sommer, Stefanie Wagner, Katharina Rox, Annabelle Varrot, Dirk Hauck, Eike Christian Wamhoff, Janine Schreiber, Thomas Ryckmans, Thomas Brunner, Christoph Rademacher, Rolf W. Hartmann, Mark Brönstrup, Anne Imberty, Alexander Titz
Abstract

The opportunistic Gram-negative bacterium Pseudomonas aeruginosa is a leading pathogen for infections of immuno-compromised patients and those suffering from cystic fibrosis. Its ability to switch from planktonic life to aggregates, forming the so-called biofilms, is a front-line mechanism of antimicrobial resistance. The bacterial carbohydrate-binding protein LecB is an integral component and necessary for biofilm formation. Here, we report a new class of drug-like low molecular weight inhibitors of the lectin LecB with nanomolar affinities and excellent receptor binding kinetics and thermodynamics. This class of glycomimetic inhibitors efficiently blocked biofilm formation of P. aeruginosa in vitro while the natural monovalent carbohydrate ligands failed. Furthermore, excellent selectivity and pharmacokinetic properties were achieved. Notably, two compounds showed good oral bioavailability, and high compound concentrations in plasma and urine were achieved in vivo.

Organisationseinheit(en)
AG Chemische Biologie
Externe Organisation(en)
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Deutsches Zentrum für Infektionsforschung (DZIF)
Université Grenoble Alpes (UGA)
Max-Planck-Institut für Kolloid- und Grenzflächenforschung
Freie Universität Berlin
F. Hoffmann-La Roche AG
Universität Konstanz
Universität des Saarlandes
Typ
Artikel
Journal
Journal of the American Chemical Society
Band
140
Seiten
2537-2545
Anzahl der Seiten
9
ISSN
0002-7863
Publikationsdatum
21.02.2018
Publikationsstatus
Veröffentlicht
Peer-reviewed
Ja
ASJC Scopus Sachgebiete
Katalyse, Chemie (insg.), Biochemie, Kolloid- und Oberflächenchemie
Elektronische Version(en)
https://doi.org/10.1021/jacs.7b11133 (Zugang: Offen)