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.

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 (FU 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)