Frontiers in Chemistry (May 2020)
Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa
- Fadi Soukarieh,
- Fadi Soukarieh,
- Ruiling Liu,
- Manuel Romero,
- Manuel Romero,
- Shaun N. Roberston,
- Shaun N. Roberston,
- William Richardson,
- Simone Lucanto,
- Simone Lucanto,
- Eduard Vico Oton,
- Naim Ruhul Qudus,
- Alaa Mashabi,
- Scott Grossman,
- Sadiqur Ali,
- Tomás Sou,
- Tomás Sou,
- Irena Kukavica-Ibrulj,
- Roger C. Levesque,
- Christel A. S. Bergström,
- Christel A. S. Bergström,
- Nigel Halliday,
- Shailesh N. Mistry,
- Jonas Emsley,
- Jonas Emsley,
- Stephan Heeb,
- Paul Williams,
- Paul Williams,
- Miguel Cámara,
- Miguel Cámara,
- Michael J. Stocks,
- Michael J. Stocks
Affiliations
- Fadi Soukarieh
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Fadi Soukarieh
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- Ruiling Liu
- School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Manuel Romero
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Manuel Romero
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- Shaun N. Roberston
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Shaun N. Roberston
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- William Richardson
- School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Simone Lucanto
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Simone Lucanto
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- Eduard Vico Oton
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Naim Ruhul Qudus
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Alaa Mashabi
- School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Scott Grossman
- School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Sadiqur Ali
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Tomás Sou
- Drug Delivery Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden
- Tomás Sou
- Pharmacometrics Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
- Irena Kukavica-Ibrulj
- Institut de Biologie Intégrative et des Systèmes, Université Laval, Quebec City, QC, Canada
- Roger C. Levesque
- Institut de Biologie Intégrative et des Systèmes, Université Laval, Quebec City, QC, Canada
- Christel A. S. Bergström
- Drug Delivery Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden
- Christel A. S. Bergström
- The Swedish Drug Delivery Center, Department of Pharmacy, Uppsala University, Uppsala, Sweden
- Nigel Halliday
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Shailesh N. Mistry
- School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Jonas Emsley
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- Jonas Emsley
- School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Stephan Heeb
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Paul Williams
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Paul Williams
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- Miguel Cámara
- School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Miguel Cámara
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- Michael J. Stocks
- The National Biofilms Innovation Centre, University of Nottingham, Nottingham, United Kingdom
- Michael J. Stocks
- School of Pharmacy, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- DOI
- https://doi.org/10.3389/fchem.2020.00204
- Journal volume & issue
-
Vol. 8
Abstract
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.
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