Disarming Pseudomonas aeruginosa: repurposing vardenafil, valsartan, and olmesartan as anti-virulence and antibiofilm agents

Abstract

The rapid emergence of antibiotic resistance represents a critical global health challenge, particularly in biofilm-associated infections caused by Pseudomonas aeruginosa (P. aeruginosa). Quorum sensing plays a pivotal role in regulating bacterial virulence and biofilm formation. Consequently, targeting quorum sensing-regulated virulence factors represents a promising anti-virulence strategy to combat antibiotic resistance. In this study, the FDA-approved drugs vardenafil, valsartan, and olmesartan did not significantly affect the growth of ten clinical P. aeruginosa isolates. At sub-inhibitory concentrations, these drugs significantly reduced the production of key virulence factors, including hemolysin, proteases, pyocyanin, lipases, as well as impairing swarming motility, and biofilm formation. Gene expression analysis confirmed marked downregulation of quorum sensing-associated genes in five selected isolates. In vivo experiments revealed a substantial reduction in bacterial pathogenicity following treatment. Molecular docking analyses further supported these findings, revealing favorable interactions of the tested drugs with key quorum sensing regulatory proteins. Collectively, these results highlight the anti-quorum sensing, anti-virulence, and antibiofilm potential of these repurposed drugs and suggest their possible application in topical formulations as adjunctive therapies to conventional antibiotics for managing severe pseudomonal infections.