Abstract
Quorum sensing (QS) inhibition by metal-antibiotic complexes is a promising strategy for the management and control of multidrug resistant Pseudomonas aeruginosa infections. We investigated the anti-quorum sensing activity of sub-minimum inhibitory concentration (sub-MIC) of copper(II) sulfate pentahydrate-ciprofloxacin (Cu-CIP) complex and free ciprofloxacin (free-CIP) against P. aeruginosa PAO1. Copper-CIP complex was synthesized and its characterization was assessed using spectroscopic methods and single crystal X-ray analysis. The effect of sub-MIC (1/4 and 1/16 MIC) concentrations of Cu-CIP and free-CIP on cell growth, biofilm formation, motility, alginate and pyocyanin production, H2O2 susceptibility and expression of QS circuit genes lasI and lasR in PAO1 was determined. Minimum inhibitory concentration of Cu-CIP complex and free-CIP was determined as 0.125 µg/ml. Copper-CIP complex did not show significant effect on the cell growth at concentrations of 1/4 and 1/16 MIC. However, sub-MIC concentrations (1/4 and 1/16 MIC) of Cu-CIP showed the significant reduction in violacein production, motility, biofilm formation, alginate and pyocyanin production and sensitivity to H2O2 in a concentration dependent manner (P < 0.001). Copper-CIP at the concentration of 1/4 MIC showed the greatest reduction in lasI and lasR transcriptional expression (89.5% and 96.2% respectively). Considering the biological effects of Cu-CIP complex and its inhibitory activity on QS related virulence traits at low concentrations (0.03 and 0.007 µg/ml), it may be used as an effective approach in the management of infections caused by P. aeruginosa.
Highlights
Pseudomonas aeruginosa as an important nosocomial pathogen can causes serious infections such as cystic fibrosis, endocarditis, bacteremia, wound, burn and urinary tract infections
Inhibition of quorum sensing by metal-drug complexes is a promising strategy for control of drug resistant bacterial infections (Driscoll et al 2007; Sabale et al 2012; Fig. 6 The subinhibitory concentrations (1/4 and 1/16 Minimum inhibitory concentration (MIC)) of ciprofloxacin (CIP) and copper-ciprofloxacin complex (Cu-CIP) inhibited QS regulated genes in treated PAO1 (*, significant, P < 0.05)
It has been found that the metal complexes of quinolones possess more biological and antibacterial activities than free quinolones (Sabale et al 2012)
Summary
Pseudomonas aeruginosa as an important nosocomial pathogen can causes serious infections such as cystic fibrosis, endocarditis, bacteremia, wound, burn and urinary tract infections. Subinhibitory concentrations of ciprofloxacin significantly decreased the virulence factors like motility, biofilm formation, and production of protease, elastase, siderophore, alginate, and rhamnolipid in P. aeruginosa (Khan et al 2017; Gupta et al 2016). The overlapping of the ligand orbital and the partial sharing of the donor groups with positive charge of the metal ion lead to reduction of the metal ion polarity It enhances delocalization of pielectrons over the whole chelate ring and increases the lipophilicity and penetration of the metal complex into the membrane lipids and blokes the binding sites of metal dependent proteins of the microorganism (Sadeek et al.2015; Sabale et al 2012; Uivarosi 2013; Khan et al 2017). This study aimed to investigated the anti-quorum sensing activity of subMIC concentrations of copper(II) sulfate pentahydrate (CuSO4·5H2O)-ciprofloxacin complex (Cu-CIP) and free ciprofloxacin (free-CIP) against P. aeruginosa PAO1
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