TY - JOUR
T1 - Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa
AU - Sabir, Shekh
AU - Suresh, Dittu
AU - Subramoni, Sujatha
AU - Das, Theerthankar
AU - Bhadbhade, Mohan
AU - Black, David St C.
AU - Rice, Scott A.
AU - Kumar, Naresh
N1 - Funding Information:
We thank the NMR, X-ray and BMSF facility, at Mark Wainwright Analytical Centre (MWAC), UNSW Sydney. S.Sabir would like to acknowledge UNSW TFS scholarship.
Funding Information:
This work was supported by a Discovery Project from Australian Research Council grant (DP180100845).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/2/1
Y1 - 2021/2/1
N2 - The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.
AB - The Pseudomonas quinolone system (pqs) is one of the key quorum sensing systems in antibiotic-resistant P. aeruginosa and is responsible for the production of virulence factors and biofilm formation. Thus, synthetic small molecules that can target the PqsR (MvfR) receptor can be utilized as quorum sensing inhibitors to treat P. aeruginosa infections. In this study, we report the synthesis of novel thioether-linked dihydropyrrol-2-one (DHP) analogues as PqsR antagonists. Compound 7g containing a 2-mercaptopyridyl linkage effectively inhibited the pqs system with an IC50 of 32 µM in P. aeruginosa PAO1. Additionally, these inhibitors significantly reduced bacterial aggregation and biofilm formation without affecting planktonic growth. The molecular docking study suggest that these inhibitors bind with the ligand binding domain of the MvfR as a competitive antagonist.
KW - Dihydropyrrol-2-one (DHP) analogues
KW - PqsR antagonist
KW - Pseudomonas aeruginosa
KW - Pseudomonas quinolone system
KW - Quorum sensing inhibitors
UR - https://www.scopus.com/pages/publications/85098972225
U2 - 10.1016/j.bmc.2020.115967
DO - 10.1016/j.bmc.2020.115967
M3 - Article
C2 - 33434766
AN - SCOPUS:85098972225
SN - 0968-0896
VL - 31
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
M1 - 115967
ER -