Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa
Roman Sommer
,
Stefanie Wagner
,
Katharina Rox
,
Annabelle Varrot
(1)
,
Dirk Hauck
,
Eike-Christian Wamhoff
,
Janine Schreiber
,
Thomas Ryckmans
,
Thomas Brunner
(2)
,
Christoph Rademacher
(3)
,
Rolf Hartmann
(4)
,
Mark Brönstrup
,
Anne Imberty
(1)
,
Alexander Titz
Roman Sommer
- Fonction : Auteur
Stefanie Wagner
- Fonction : Auteur
- PersonId : 1136633
Katharina Rox
- Fonction : Auteur
Annabelle Varrot
- Fonction : Auteur
- PersonId : 21417
- IdHAL : annabelle-varrot
- ORCID : 0000-0001-6667-8162
- IdRef : 138538808
Dirk Hauck
- Fonction : Auteur
Eike-Christian Wamhoff
- Fonction : Auteur
Janine Schreiber
- Fonction : Auteur
Thomas Ryckmans
- Fonction : Auteur
Mark Brönstrup
- Fonction : Auteur
Anne Imberty
- Fonction : Auteur
- PersonId : 174401
- IdHAL : anne-imberty
- ORCID : 0000-0001-6825-9527
- IdRef : 033866015
Alexander Titz
- Fonction : Auteur
- PersonId : 792961
- ORCID : 0000-0001-7408-5084
- IdRef : 248591932
Résumé
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.
Domaines
ChimieFormat du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa
|
Résumé |
en
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.
|
Auteur(s) |
Roman Sommer
, Stefanie Wagner
, Katharina Rox
, Annabelle Varrot
1
, Dirk Hauck
, Eike-Christian Wamhoff
, Janine Schreiber
, Thomas Ryckmans
, Thomas Brunner
2
, Christoph Rademacher
3
, Rolf Hartmann
4
, Mark Brönstrup
, Anne Imberty
1
, Alexander Titz
1
CERMAV -
Centre de Recherches sur les Macromolécules Végétales
( 1041817 )
- CS40700, 38041 Grenoble cedex 9
- France
2
Division of Immunopathology
( 86993 )
- Bern
- Suisse
3
Department of Biomolecular Systems [Potsdam]
( 215186 )
- Am Mühlenberg 1 D-14476 Potsdam
- Allemagne
4
Jena Optronik -
Jena Optronik GmbH
( 236075 )
- Pruessingstrasse 41 07745 Jena - Germany
- Allemagne
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Date de publication |
2018-02-07
|
Volume |
140
|
Numéro |
7
|
Page/Identifiant |
2537-2545
|
Domaine(s) |
|
Projet(s) ANR |
|
DOI | 10.1021/jacs.7b11133 |
Origine :
Publication financée par une institution
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