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Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa

Soukarieh, Fadi; Liu, Ruiling; Romero, Manuel; Roberston, Shaun N.; Richardson, William; Lucanto, Simone; Oton, Eduard Vico; Qudus, Naim Ruhul; Mashabi, Alaa; Grossman, Scott; Ali, Sadiqur; Sou, Tom�s; Kukavica-Ibrulj, Irena; Levesque, Roger C.; Bergstrom, Christel A.S.; Halliday, Nigel; Mistry, Shailesh N.; Emsley, Jonas; Heeb, Stephan; Williams, Paul; C�mara, Miguel; Stocks, Michael J.

Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa Thumbnail


Authors

Ruiling Liu

Manuel Romero

Shaun N. Roberston

William Richardson

Simone Lucanto

Eduard Vico Oton

Naim Ruhul Qudus

Alaa Mashabi

Scott Grossman

Sadiqur Ali

Tom�s Sou

Irena Kukavica-Ibrulj

Roger C. Levesque

Christel A.S. Bergstrom

Nigel Halliday



Abstract

© Copyright © 2020 Soukarieh, Liu, Romero, Roberston, Richardson, Lucanto, Oton, Qudus, Mashabi, Grossman, Ali, Sou, Kukavica-Ibrulj, Levesque, Bergström, Halliday, Mistry, Emsley, Heeb, Williams, Cámara and Stocks. Current treatments for Pseudomonas aeruginosa infections are becoming less effective because of the increasing rates of multi-antibiotic resistance. Pharmacological targeting of virulence through inhibition of quorum sensing (QS) dependent virulence gene regulation has considerable therapeutic potential. In P. aeruginosa, the pqs QS system regulates the production of multiple virulence factors as well as biofilm maturation and is a promising approach for developing antimicrobial adjuvants for combatting drug resistance. In this work, we report the hit optimisation for a series of potent novel inhibitors of PqsR, a key regulator of the pqs system, bearing a 2-((5-methyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio) acetamide scaffold. The initial hit compound 7 (PAO1-L IC50 0.98 ± 0.02 μM, PA14 inactive at 10 μM) was obtained through a virtual screening campaign performed on the PqsR ligand binding domain using the University of Nottingham Managed Chemical Compound Collection. Hit optimisation gave compounds with enhanced potency against strains PAO1-L and PA14, evaluated using P. aeruginosa pqs-based QS bioreporter assays. Compound 40 (PAO1-L IC50 0.25 ± 0.12 μM, PA14 IC50 0.34 ± 0.03 μM) is one of the most potent PqsR antagonists reported showing significant inhibition of P. aeruginosa pyocyanin production and pqs system signaling in both planktonic cultures and biofilms. The co-crystal structure of 40 with the PqsR ligand binding domain revealed the specific binding interactions occurring between inhibitor and this key regulatory protein.

Citation

Soukarieh, F., Liu, R., Romero, M., Roberston, S. N., Richardson, W., Lucanto, S., Oton, E. V., Qudus, N. R., Mashabi, A., Grossman, S., Ali, S., Sou, T., Kukavica-Ibrulj, I., Levesque, R. C., Bergstrom, C. A., Halliday, N., Mistry, S. N., Emsley, J., Heeb, S., Williams, P., …Stocks, M. J. (2020). Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa. Frontiers in Chemistry, 8, Article 204. https://doi.org/10.3389/fchem.2020.00204

Journal Article Type Article
Acceptance Date Mar 4, 2020
Online Publication Date May 4, 2020
Publication Date May 4, 2020
Deposit Date Apr 27, 2020
Publicly Available Date May 5, 2020
Journal Frontiers in Chemistry
Electronic ISSN 2296-2646
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 8
Article Number 204
DOI https://doi.org/10.3389/fchem.2020.00204
Keywords Pseudomonas aeruginosa; PqsR; MvfR; Pseudomonas quinolone signal (PQS); alkylquinolone; biofilms; quorum sensing inhibition; quorum quenching
Public URL https://nottingham-repository.worktribe.com/output/4348888
Publisher URL https://www.frontiersin.org/articles/10.3389/fchem.2020.00204/full

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