Investigating Chlorpromazine’s Role in Attenuating Quorum Sensing and Biofilm in Gram-negative Bacteria

Antimicrobial resistance (AMR) is a major health threat that reduces the effectiveness of antibiotics and complicates infection treatment. The WHO warns that without urgent action, common infections could become fatal. Factors like antibiotic overuse contribute to resistant bacteria, leading to increased healthcare costs and mortality. Quorum sensing (QS) enhances bacterial survival and pathogenicity through coordinated behaviors, such as biofilm formation. Targeting QS and biofilms offers a promising strategy to manage infections and combat AMR, utilizing natural and synthetic inhibitors to disrupt bacterial communication. This study examined the inhibitory effects of chlorpromazine on QS-regulated virulence in various pathogenic bacteria. The findings demonstrate that chlorpromazine significantly reduces the violacein pigment of C. violaceum 12472 by 73.15%. In S. marcescens MTCC 97, chlorpromazine inhibited prodigiosin production by 69.09%, protease production by 61.90% and swimming motility by 91.63%. Additionally, in P. aeruginosa PAO1, chlorpromazine treatment resulted in substantial decreases in several virulence factors. The biofilms of test bacteria were reduced at sub-MICs. Chlorpromazine was found to interact at the active site of LasR, CviR and RhlR with energies ranging from −6.4 kcal/mol to −7.4 kcal/mol. Molecular simulations validated the stability of complexes when simulated at physiological conditions. The study shows the potential of chlorpromazine as a QS inhibitor, offering a promising strategy for managing bacterial infections by targeting virulence factors rather than relying solely on traditional antibiotics. Further research is required to explore the mechanisms of chlorpromazine’s action and its applicability in clinical settings.