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

authored by

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.

External Organisation(s)

Helmholtz Centre for Infection Research (HZI)
German Center for Infection Research (DZIF)
University Grenoble-Alpes (UGA)
Max Planck Institute of Colloids and Interfaces
Freie Universität Berlin (FU Berlin)
F. Hoffmann-La Roche AG
University of Konstanz
Saarland University

Type

Article

Journal

Journal of the American Chemical Society

Volume

140

Pages

2537-2545

No. of pages

9

ISSN

0002-7863

Publication date

21.02.2018

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Catalysis, Chemistry(all), Biochemistry, Colloid and Surface Chemistry

Electronic version(s)

https://doi.org/10.1021/jacs.7b11133 (Access: Open)