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

DOI: 10.1016/j.ejmech.2020.112778 DOI Help

Authors: Scott Grossman (University of Nottingham Biodiscovery Institute) , Fadi Soukarieh (University of Nottingham Biodiscovery Institute) , William Richardson (University of Nottingham Biodiscovery Institute) , Ruiling Liu (University of Nottingham Biodiscovery Institute) , Alaa Mashabi (University of Nottingham Biodiscovery Institute) , Jonas Emsley (University of Nottingham Biodiscovery Institute) , Paul Williams (University of Nottingham Biodiscovery Institute) , Miguel Cámara (University of Nottingham Biodiscovery Institute) , Michael J. Stocks (University of Nottingham Biodiscovery Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2020
Diamond Proposal Number(s): 19880

Open Access Open Access

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.

Journal Keywords: Pseudomonas aeruginosa; quorum sensing; inhibitors; X-ray crystal structure; PqsR

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 09/09/2020 14:23


Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)