Enhanced antimicrobial activity of naringin-ciprofloxacin combination against Pseudomonas aeruginosa PAO1: Unveiling quorum-sensing mediated molecular mechanisms in biofilm formation and virulence

Abstract

Natural products offer a wealth of potential antimicrobial agents that target various cellular signalling pathways of bacterial pathogens linked to public health issues, especially for managing biofilm-associated infections caused by Pseudomonas aeruginosa . Naringin, a flavanone glycoside, alone or in combination with ciprofloxacin was reported to inhibit biofilm development effectively in P. aeruginosa . However, the molecular mechanisms behind the antibiofilm activities of naringin are yet to be fully understood. This study was performed to unveil the mechanistic role of naringin-ciprofloxacin (NC) combinations for its antibiofilm and antivirulence attributes using P. aeruginosa PAO1 as the model organism. NC combinations interfered with the production of different virulence factors in P. aeruginosa . The RT-qPCR analysis suggested that NC combinations notably decreased the expression of lasI and rhlI , the autoinducer synthase genes, and the expression of lasR and rhlR as well. Additionally, molecular docking analysis showed naringin could disrupt the interactions between LasI-LasR, and RhlI-RhlR, thus potentially could affect QS-network of P. aeruginosa . The change in the expression and interaction pattern of the QS regulator genes by the NC combinations may account for the reduction in biofilm formation and pathogenic behaviour in P. aeruginosa . Thus, the combination of naringin and ciprofloxacin might offer a promising alternative to restrict the biofilm development by P. aeruginosa , and could serve as a reference for addressing antibiotic resistance for managing biofilm-assisted pseudomonad infections. • Naringin with ciprofloxacin additively inhibits biofilm formation in P. aeruginosa. • Sub-MIC combinations significantly alter motility and virulence factor production. • Combinations alters the expression levels of QS-associated genes. • Molecular docking shows QS-regulatory proteins are the target of naringin.