Towards Translation of PqsR Inverse Agonists: From In Vitro Efficacy Optimization to In Vivo Proof-of-Principle

Area of Science:

• Microbiology
• Drug Discovery
• Infectious Diseases

Background:

• Pseudomonas aeruginosa (PA) is an opportunistic pathogen causing severe infections.
• PA exhibits significant antibiotic resistance, necessitating alternative treatments.
• Quorum sensing (QS) regulates PA virulence and biofilm formation, making it a therapeutic target.

Purpose of the Study:

• To design and optimize novel Pseudomonas quinolone signaling receptor (PqsR) inverse agonists.
• To evaluate the efficacy of these compounds against PA pathogenicity and antibiotic resistance.
• To provide a potential adjunctive therapy for PA infections.

Main Methods:

• Rational drug design and lead optimization of pyrimidine-based PqsR inverse agonists.
• In vitro assays for pyocyanin suppression and biofilm inhibition.
• In vivo efficacy studies in a murine neutropenic thigh infection model.
• Pharmacokinetic and safety pharmacology profiling.

Main Results:

• A frontrunner compound with a pyrimidine scaffold demonstrated high in vitro and in vivo efficacy.
• The compound effectively suppressed pyocyanin and synergized with tobramycin against PA biofilms.
• Activity was confirmed against clinical isolates from bronchiectasis patients.
• Favorable pharmacokinetics and safety profiles were observed.

Conclusions:

• The developed PqsR inverse agonist represents a promising therapeutic candidate for Pseudomonas aeruginosa infections.
• This compound can disarm bacteria by interfering with QS, offering an alternative to traditional antibiotics.
• The results support its potential use in adjunctive treatment strategies, enhancing current therapies.