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Eur J Med Chem. 2015;96:14-21. doi: 10.1016/j.ejmech.2015.04.007. Epub 2015 Apr 6.

Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa.

Author information

1
Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany.
2
PharmBioTec GmbH, Science Park 1, 66123 Saarbrücken, Germany.
3
Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany. Electronic address: rolf.hartmann@helmholtz-hzi.de.

Abstract

Pseudomonas aeruginosa employs a quorum sensing (QS) communication system that makes use of small diffusible molecules. Among other effects, the QS system coordinates the formation of biofilm which decisively contributes to difficulties in the therapy of Pseudomonas infections. The present work deals with the structure-activity exploration of ureidothiophene-2-carboxylic acids as inhibitors of PqsD, a key enzyme in the biosynthetic pathway of signal molecules in the Pseudomonas QS system. We describe an improvement of the inhibitory activity by successfully combining features from two different PqsD inhibitor classes. Furthermore the functional groups, which are responsible for the inhibitory potency, were identified. Moreover, the inability of the new inhibitors, to prevent signal molecule formation in whole cell assays, is discussed.

KEYWORDS:

Antibacterial agents; Bacterial cell-to-cell communication; Pseudomonas aeruginosa; Quorum sensing; Ureidothiophene-2-carboxylic acids

PMID:
25874327
DOI:
10.1016/j.ejmech.2015.04.007
[Indexed for MEDLINE]

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