AUTHOR=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 Tomás , Kukavica-Ibrulj Irena , Levesque Roger C. , Bergström Christel A. S. , Halliday Nigel , Mistry Shailesh N. , Emsley Jonas , Heeb Stephan , Williams Paul , Cámara Miguel , Stocks Michael J. 

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

JOURNAL=Frontiers in Chemistry

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.00204

DOI=10.3389/fchem.2020.00204

ISSN=2296-2646

ABSTRACT=<p>Current treatments for <italic>Pseudomonas aeruginosa</italic> 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 <italic>P. aeruginosa</italic>, the <italic>pqs</italic> 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 <italic>pqs</italic> system, bearing a 2-((5-methyl-5<italic>H</italic>-[1,2,4]triazino[5,6-<italic>b</italic>]indol-3-yl)thio) acetamide scaffold. The initial hit compound <bold>7</bold> (PAO1-L IC<sub>50</sub> 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 <italic>P. aeruginosa pqs</italic>-based QS bioreporter assays. Compound <bold>40</bold> (PAO1-L IC<sub>50</sub> 0.25 ± 0.12 μM, PA14 IC<sub>50</sub> 0.34 ± 0.03 μM) is one of the most potent PqsR antagonists reported showing significant inhibition of <italic>P. aeruginosa</italic> pyocyanin production and <italic>pqs</italic> system signaling in both planktonic cultures and biofilms. The co-crystal structure of <bold>40</bold> with the PqsR ligand binding domain revealed the specific binding interactions occurring between inhibitor and this key regulatory protein.</p>