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

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 antimi...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2018-02, Vol.140 (7), p.2537-2545
Main Authors: Sommer, Roman, Wagner, Stefanie, Rox, Katharina, Varrot, Annabelle, Hauck, Dirk, Wamhoff, Eike-Christian, Schreiber, Janine, Ryckmans, Thomas, Brunner, Thomas, Rademacher, Christoph, Hartmann, Rolf W, Brönstrup, Mark, Imberty, Anne, Titz, Alexander
Format: Article
Language:English
Subjects:
Administration, Oral
Biofilms - drug effects
Biological Availability
Chemical Sciences
Cinnamates - administration & dosage
Cinnamates - chemistry
Cinnamates - pharmacology
Dose-Response Relationship, Drug
Kinetics
Lectins - antagonists & inhibitors
Lectins - metabolism
Molecular Conformation
Pseudomonas aeruginosa - drug effects
Pseudomonas aeruginosa - metabolism
Structure-Activity Relationship
Sulfonamides - administration & dosage
Sulfonamides - chemistry
Sulfonamides - pharmacology
Thermodynamics
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.7b11133