Anti-biofilm Agents against Pseudomonas aeruginosa : A Structure–Activity Relationship Study of C -Glycosidic LecB Inhibitors
Roman Sommer
(1, 2)
,
Katharina Rox
(2)
,
Stefanie Wagner
(1)
,
Dirk Hauck
(1)
,
Sarah Henrikus
(1)
,
Shelby Newsad
(1)
,
Tatjana Arnold
(2)
,
Thomas Ryckmans
(3)
,
Mark Brönstrup
(2)
,
Anne Imberty
(4)
,
Annabelle Varrot
(4)
,
Rolf Hartmann
(5)
,
Alexander Titz
(1)
1
HIPS -
Chemical Biology of Carbohydrates, Helmholtz Institute for Pharmaceutical Research Saarland
2 DZIF - German Center for Infection Research - partner site Hannover-Braunschweig
3 Roche Innovation Center [Basel, Switzerland]
4 CERMAV - Centre de Recherches sur les Macromolécules Végétales
5 HIPS - Helmholtz Institute for Pharmaceutical Research Saarland
2 DZIF - German Center for Infection Research - partner site Hannover-Braunschweig
3 Roche Innovation Center [Basel, Switzerland]
4 CERMAV - Centre de Recherches sur les Macromolécules Végétales
5 HIPS - Helmholtz Institute for Pharmaceutical Research Saarland
Stefanie Wagner
- Fonction : Auteur
- PersonId : 1136633
Anne Imberty
- Fonction : Auteur
- PersonId : 174401
- IdHAL : anne-imberty
- ORCID : 0000-0001-6825-9527
- IdRef : 033866015
Annabelle Varrot
- Fonction : Auteur
- PersonId : 21417
- IdHAL : annabelle-varrot
- ORCID : 0000-0001-6667-8162
- IdRef : 138538808
Alexander Titz
- Fonction : Auteur
- PersonId : 1055733
Résumé
Biofilm formation is a key mechanism of antimicrobial resistance. We have recently reported two classes of orally bioavailable C-glycosidic inhibitors of the Pseudomonas aeruginosa lectin LecB with anti-biofilm activity. They proved efficient in target binding, were metabolically stable, non-toxic, selective and potent in inhibiting formation of bacterial biofilm. Here, we designed and synthesized 6 new carboxamides and 24 new sulfonamides for a detailed structure-activity-relationship for two clinically representative LecB variants. Sulfonamides generally showed higher inhibition compared to carboxamides which was rationalized based on crystal structure analyses. Substitutions at the thiophenesulfonamide increased binding through extensive contacts with a lipophilic protein patch. These metabolically stable compounds showed a further increase in potency towards the target and in biofilm inhibition assays. In general, we established the structure-activity relationship for these promising anti-biofilm agents and showed that modification of the sulfonamide residue bears future optimization potential. 1
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Anti-biofilm Agents against Pseudomonas aeruginosa : A Structure–Activity Relationship Study of C -Glycosidic LecB Inhibitors
|
Résumé |
en
Biofilm formation is a key mechanism of antimicrobial resistance. We have recently reported two classes of orally bioavailable C-glycosidic inhibitors of the Pseudomonas aeruginosa lectin LecB with anti-biofilm activity. They proved efficient in target binding, were metabolically stable, non-toxic, selective and potent in inhibiting formation of bacterial biofilm. Here, we designed and synthesized 6 new carboxamides and 24 new sulfonamides for a detailed structure-activity-relationship for two clinically representative LecB variants. Sulfonamides generally showed higher inhibition compared to carboxamides which was rationalized based on crystal structure analyses. Substitutions at the thiophenesulfonamide increased binding through extensive contacts with a lipophilic protein patch. These metabolically stable compounds showed a further increase in potency towards the target and in biofilm inhibition assays. In general, we established the structure-activity relationship for these promising anti-biofilm agents and showed that modification of the sulfonamide residue bears future optimization potential. 1
|
Auteur(s) |
Roman Sommer
1, 2
, Katharina Rox
2
, Stefanie Wagner
1
, Dirk Hauck
1
, Sarah Henrikus
1
, Shelby Newsad
1
, Tatjana Arnold
2
, Thomas Ryckmans
3
, Mark Brönstrup
2
, Anne Imberty
4
, Annabelle Varrot
4
, Rolf Hartmann
5
, Alexander Titz
1
1
HIPS -
Chemical Biology of Carbohydrates, Helmholtz Institute for Pharmaceutical Research Saarland
( 545626 )
- 66123 Saarbrucken
- Allemagne
2
DZIF -
German Center for Infection Research - partner site Hannover-Braunschweig
( 522158 )
- Allemagne
3
Roche Innovation Center [Basel, Switzerland]
( 558311 )
- Suisse
4
CERMAV -
Centre de Recherches sur les Macromolécules Végétales
( 1041817 )
- CS40700, 38041 Grenoble cedex 9
- France
5
HIPS -
Helmholtz Institute for Pharmaceutical Research Saarland
( 572437 )
- Helmholtz-Institut für Pharmazeutische Forschung Saarland (HIPS)
Campus E8.1
66123 Saarbrücken
- Allemagne
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Date de publication |
2019-09-17
|
Volume |
62
|
Numéro |
20
|
Page/Identifiant |
9201-9216
|
Domaine(s) |
|
Collaboration/Projet |
|
Projet(s) ANR |
|
DOI | 10.1021/acs.jmedchem.9b01120 |
Origine :
Fichiers produits par l'(les) auteur(s)
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