2. Academic Validation
  3. Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR

Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR

  • Eur J Med Chem. 2020 Dec 15;208:112778. doi: 10.1016/j.ejmech.2020.112778.
Scott Grossman 1,  Fadi Soukarieh 2,  William Richardson 1,  Ruiling Liu 1,  Alaa Mashabi 1,  Jonas Emsley 3,  Paul Williams 2,  Miguel Cámara 2,  Michael J Stocks 4
Affiliations

Affiliations

  • 1 School of Pharmacy, University of Nottingham Biodiscovery Institute, University Park, Nottingham, Nottinghamshire, NG7 2RD, UK.
  • 2 School of Life Sciences, University of Nottingham Biodiscovery Institute, University Park, Nottingham, Nottinghamshire, NG7 2RD, UK; National Biofilms Innovation Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, Nottinghamshire, NG7 2RD, UK.
  • 3 School of Pharmacy, University of Nottingham Biodiscovery Institute, University Park, Nottingham, Nottinghamshire, NG7 2RD, UK; National Biofilms Innovation Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, Nottinghamshire, NG7 2RD, UK.
  • 4 School of Pharmacy, University of Nottingham Biodiscovery Institute, University Park, Nottingham, Nottinghamshire, NG7 2RD, UK; National Biofilms Innovation Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, Nottinghamshire, NG7 2RD, UK. Electronic address: [email protected].
PMID: 32927392 DOI: 10.1016/j.ejmech.2020.112778
Abstract

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:PpqsA-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.

Keywords

Inhibitors; PqsR; Pseudomonas aeruginosa; Quorum sensing; X-ray crystal structure.

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