Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 208, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112778
Keywords
Pseudomonas aeruginosa; Quorum sensing; Inhibitors; X-ray crystal structure; PqsR
Categories
Funding
- Wellcome Trust [108876/B/15/Z]
- JPI-AMR/MRC [MR/N501852/1]
- National Biofilms Innovation Centre (NBIC) - Biotechnology and Biological Sciences Research Council
- InnovateUK
- Hartree Centre [BB/R012415/1]
- BBSRC [BB/R012415/1] Funding Source: UKRI
- Wellcome Trust [108876/B/15/Z] Funding Source: Wellcome Trust
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Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50 < 300 nM) in a whole-cell assay, using a mCTX:P-pqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation. (c) 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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