Pathway-Centric Structure-Based Multi-Target Compound Screening for Anti-Virulence Drug Repurposing.

Area of Science:

• Microbiology and Infectious Diseases
• Pharmacology and Drug Discovery
• Computational Chemistry

Background:

• The rise of antibiotic-resistant bacteria, or superbugs, presents a critical global health challenge, necessitating novel therapeutic strategies.
• Targeting bacterial virulence factors, such as pyocyanin produced by *Pseudomonas aeruginosa*, offers a promising approach to combat drug-resistant infections.
• Pyocyanin is a key virulence factor in *Pseudomonas aeruginosa* infections, making its biosynthesis pathway a potential target for anti-infective drug development.

Purpose of the Study:

• To discover novel therapeutics that inhibit the phenazine biosynthesis pathway, a critical virulence mechanism in *Pseudomonas aeruginosa*.
• To identify lead compounds capable of targeting multiple enzymes within the phenazine biosynthesis pathway to combat drug resistance.
• To apply a structure-based drug design strategy for polypharmacological drug repositioning.

Main Methods:

• Screened 2004 clinical and pre-clinical drugs using a novel protein-ligand docking procedure.
• Focused on targeting multiple enzymes (aroQ, phzG, phzS) within the bacterial phenazine biosynthesis pathway.
• Employed a multi-target, structure-based drug design approach.

Main Results:

• Identified kinase inhibitors, with Lifirafenib as a notable example, as promising compounds for inhibiting key enzymes in phenazine biosynthesis.
• The identified compounds show potential for targeting multiple enzymes, which could be more effective in combating resistance than single-target approaches.
• The study provides a systematic strategy for polypharmacological drug repositioning applicable to other biological pathways.

Conclusions:

• Kinase inhibitors, particularly Lifirafenib, represent promising lead compounds for developing new anti-infective therapeutics against *Pseudomonas aeruginosa*.
• Inhibiting multiple targets within a pathway is a viable strategy to enhance therapeutic efficacy and mitigate the emergence of drug resistance.
• The developed multi-target drug design strategy offers a systematic framework for drug repositioning and tackling other complex biological pathways.