Development and evaluation of new nanoformulated thiolactone derivatives for enhanced disruption of pseudomonal biofilms

Abstract

Pseudomonas aeruginosa (P. aeruginosa) is a formidable, antibiotic-resistant pathogen responsible for severe infections, particularly due to its ability to form protective biofilms mediated by the quorum sensing (QS) system, a cell-to-cell communication mechanism essential for biofilm formation and virulence. Herein, we developed a novel nanoformulation of thiolactone derivatives designed to target the QS system of P. aeruginosa. Specifically, chlorothiolactone (CTL) compounds (mCTL, 4a and pCTL, 4b) were encapsulated within biocompatible pluronic nanoparticles to enhance their delivery and efficacy. Our nanoformulation demonstrated efficient delivery of the designated molecules, leading to inhibition of the LasR receptor, a key regulator of QS, and subsequent disruption of biofilm formation. Our results revealed that the nanoparticle-formulated CTL derivatives exhibited superior activity in influencing the kinetics of P. aeruginosa biofilm and suppressing the virulence factors of P. aeruginosa, including pyocyanin and rhamnolipid production, compared to their free counterparts. Preliminary mechanistic studies indicated that the nanoformulation significantly reduced exopolysaccharide production, a critical component for biofilm integrity. Collectively, these findings underscore the potential of 4a-NPs and 4b-NPs as promising therapeutic candidates for combating P. aeruginosa infections by targeting its QS-mediated biofilm formation and virulence.