Phenazine Biosynthesis Inhibitors as Pseudomonas aeruginosa Antivirulence Agents

Abstract Phenazines are redox-active secondary metabolites produced by a variety of bacteria, including Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen associated with severe, often chronic infections and particularly notorious for its multiple resistance mechanisms. A major contributor to P. aeruginosa virulence and resistance is the production of phenazine-derived metabolites such as pyocyanin, which play central roles in biofilm formation, redox homeostasis, and host tissue damage. Consequently, inhibition of phenazine biosynthesis may be an attractive pathoblocker strategy aimed at attenuating bacterial virulence without exerting bactericidal pressure, thus reducing the development of drug resistance. Over the past years, considerable progress has been made in the identification and characterization of small-molecule inhibitors targeting this pathway. These advances have been driven by interdisciplinary efforts, with medicinal chemistry, chemical biology, and structural biology providing key insights into target tractability, ligand binding modes, and structure–activity relationships. In this review, we summarize recent developments in phenazine biosynthesis inhibition, highlighting representative inhibitors and discussing biological and structural data for enzymes across the pathway.