Quinazolinone-Based PqsR Modulators Suppress Quorum-Sensing-Driven Virulence in Pseudomonas aeruginosa

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• * Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen requiring novel antimicrobial treatments.
• * Virulence factor production in P. aeruginosa is regulated by the pqs quorum sensing (QS) system.
• * The pqs QS system utilizes 2-alkyl-4-quinolone (AQ) signal molecules and the PqsR transcriptional regulator.

Purpose of the Study:

• * To design and synthesize novel quinazolinone-based modulators targeting the PqsR regulator.
• * To evaluate the anti-PqsR activity of synthesized compounds.
• * To assess the impact of these compounds on PqsR-controlled virulence factor production.

Main Methods:

• * Design and synthesis of quinazolinone derivatives.
• * In vitro evaluation of PqsR modulatory activity (submicromolar range).
• * Assessment of virulence factor inhibition in laboratory and clinical isolates of P. aeruginosa.

Main Results:

• * Identification of two novel quinazolinone-based compounds with potent anti-PqsR activity.
• * Demonstrated submicromolar inhibitory concentrations against PqsR.
• * Successful inhibition of PqsR-controlled virulence factors in various P. aeruginosa strains.

Conclusions:

• * Novel quinazolinone derivatives effectively modulate the PqsR regulator.
• * These compounds represent promising leads for developing new antimicrobial therapies against P. aeruginosa.
• * Inhibition of the pqs QS system offers a viable strategy to combat P. aeruginosa infections.