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

• Published in: Journal of the American Chemical Society Vol. 140; no. 7; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.02.2018; Amer Chemical Soc
• Subjects: Administration, Oral; Biofilms - drug effects; Biological Availability; Chemical Sciences; Chemistry; Chemistry, Multidisciplinary; Cinnamates - administration & dosage; Cinnamates - chemistry; Cinnamates - pharmacology; Dose-Response Relationship, Drug; Kinetics; Lectins - antagonists & inhibitors; Lectins - metabolism; Molecular Conformation; Physical Sciences; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - metabolism; Science & Technology; Structure-Activity Relationship; Sulfonamides - administration & dosage; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thermodynamics; INFECTIONS; GRAM-NEGATIVE BACTERIA; RECOGNITION; LIGANDS; STRUCTURAL BASIS; RESISTANCE; BINDING; DERIVATIVES; LECTIN PA-IIL; DISCOVERY
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.7b11133

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.