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Design and Evaluation of New Quinazolin-4(3 H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa

Soukarieh, Fadi; Mashabi, Alaa; Richardson, William; Oton, Eduard Vico; Romero, Manuel; Roberston, Shaun N.; Grossman, Scott; Sou, Tomas; Liu, Ruiling; Halliday, Nigel; Kukavica-Ibrulj, Irena; Levesque, Roger C.; Bergstrom, Christel A. S.; Kellam, Barrie; Emsley, Jonas; Heeb, Stephan; Williams, Paul; Stocks, Michael J.; Cámara, Miguel

Design and Evaluation of New Quinazolin-4(3 H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa Thumbnail


Alaa Mashabi

William Richardson

Eduard Vico Oton

Manuel Romero

Shaun N. Roberston

Scott Grossman

Tomas Sou

Ruiling Liu

Nigel Halliday

Irena Kukavica-Ibrulj

Roger C. Levesque

Christel A. S. Bergstrom

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Professor of Medicinal Chemistry

Professor of Macromolecular Crystallography

Professor of Molecular Microbiology

Professor of Medicinal Chemistry and Drug Discovery

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Professor of Molecular Microbiology


P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. One such approach is to interfere with the PA pqs quorum sensing system which upon the interaction of PqsR, a Lys-R type transcriptional regulator, with its cognate signal molecules 4-hydroxy-2-heptylquinoline (HHQ) and 2-heptyl-3-hydroxy-4-quinolone (PQS), governs multiple virulence traits and host-microbe interactions. In this study, we report the hit identification and optimization of PqsR antagonists using virtual screening coupled with whole cell assay validation. The optimized hit compound 61 ((R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-hydroxypropoxy)phenyl)acetonitrile) was found to inhibit the expression of the PA PpqsA promoter controlled by PqsR with an IC50 of 1 μM. Using isothermal titration calorimetry, a Kd of 10 nM for the PqsR ligand binding domain (PqsRLBD) was determined for 61. Furthermore, the crystal structure of 61 with PqsRLBD was attained with a resolution of 2.65 Å. Compound 61 significantly reduced levels of pyocyanin, PQS, and HHQ in PAO1-L, PA14 lab strains and PAK6085 clinical isolate. Furthermore, this compound potentiated the effect of ciprofloxacin in early stages of biofilm treatment and in Galleria mellonella infected with PA. Altogether, this data shows 61 as a potent PqsR inhibitor with potential for hit to lead optimization toward the identification of a PA QS inhibitor which can be advanced into preclinical development.

Journal Article Type Article
Acceptance Date Jun 11, 2021
Online Publication Date Aug 17, 2021
Publication Date Sep 10, 2021
Deposit Date Jun 18, 2021
Publicly Available Date Aug 18, 2022
Journal ACS Infectious Diseases
Electronic ISSN 2373-8227
Publisher American Chemical Society (ACS)
Peer Reviewed Peer Reviewed
Volume 7
Issue 9
Pages 2666-2685
Keywords Infectious Diseases
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