Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa

Shekh Sabir; Dittu Suresh; Sujatha Subramoni; Theerthankar Das; Mohan Bhadbhade; David StC Black; Scott A Rice; Naresh Kumar

doi:10.1016/j.bmc.2020.115967

Thioether-linked dihydropyrrol-2-one analogues as PqsR antagonists against antibiotic resistant Pseudomonas aeruginosa

Bioorg Med Chem. 2021 Feb 1:31:115967. doi: 10.1016/j.bmc.2020.115967. Epub 2021 Jan 1.

Authors

Shekh Sabir¹, Dittu Suresh², Sujatha Subramoni³, Theerthankar Das⁴, Mohan Bhadbhade⁵, David StC Black⁶, Scott A Rice⁷, Naresh Kumar⁸

Affiliations

¹ School of Chemistry, The University of New South Wales, NSW 2052 Sydney, Australia. Electronic address: s.sabir@student.unsw.edu.au.
² School of Chemistry, The University of New South Wales, NSW 2052 Sydney, Australia.
³ Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, 637551 Singapore, Singapore. Electronic address: subramoni@ntu.edu.sg.
⁴ Department of Infectious Diseases and Immunology, School of Medical Sciences, The University of Sydney, NSW 2006 Sydney, Australia. Electronic address: das.ashishkumar@sydney.edu.au.
⁵ Mark Wainwright Analytical Centre, UNSW Sydney, Australia. Electronic address: m.bhadbhade@unsw.edu.au.
⁶ School of Chemistry, The University of New South Wales, NSW 2052 Sydney, Australia. Electronic address: d.black@unsw.edu.au.
⁷ Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, 637551 Singapore, Singapore. Electronic address: rscott@ntu.edu.sg.
⁸ School of Chemistry, The University of New South Wales, NSW 2052 Sydney, Australia. Electronic address: n.kumar@unsw.edu.au.

PMID: 33434766
DOI: 10.1016/j.bmc.2020.115967

Abstract

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.

Keywords: Dihydropyrrol-2-one (DHP) analogues; PqsR antagonist; Pseudomonas aeruginosa; Pseudomonas quinolone system; Quorum sensing inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Resistance, Bacterial / drug effects*
Microbial Sensitivity Tests
Molecular Structure
Pseudomonas aeruginosa / drug effects*
Pyrroles / chemistry
Pyrroles / pharmacology*
Quorum Sensing / drug effects
Structure-Activity Relationship
Sulfides / chemistry
Sulfides / pharmacology*

Substances

Anti-Bacterial Agents
Pyrroles
Sulfides