Quorum Sensing Inhibiting Activity of Cefoperazone and Its Metallic Derivatives on Pseudomonas aeruginosa

Abstract

The last decade has witnessed a massive increase in the rate of mortalities caused by multidrug-resistant Pseudomonas aeruginosa. Therefore, developing new strategies to control virulence factors and pathogenicity has received much attention. One of these strategies is quorum sensing inhibition (QSI) which was developed to control Pseudomonas infection. This study aims to validate the effect of one of the most used β-lactam antibiotics; cefoperazone (CFP) and its metallic-derivatives on quorum sensing (QS) and virulence factors of P. aeruginosa. Assessment of quorum sensing inhibitory activity of CFP, cefoperazone Iron complex (CFPF) and cefoperazone Cobalt complex (CFPC) was performed by using reporter strain Chromobacterium violaceum ATCC 12472. Minimal inhibitory concentration (MIC) was carried out by the microbroth dilution method. The influence of sub-MICs (1/4 and 1/2 MICs) of CFP, CFPF and CFPC on virulence factors of P. aeruginosa was evaluated. Data was confirmed on the molecular level by RT-PCR. Also, molecular docking analysis was conducted to figure out the possible mechanisms of QSI. CFP, CFPF, and CFPC inhibited violacein pigment production of C. violaceum ATCC 12472. Sub-MICs of CFP (128- 256 μg/mL), and significantly low concentrations of CFPC (0.5- 16 μg/mL) and CFPF (0.5- 64 μg/mL) reduced the production of QS related virulence factors such as pyocyanin, protease, hemolysin and eliminated biofilm assembly by P. aeruginosa standard strains PAO1 and PA14, and P. aeruginosa clinical isolates Ps1, Ps2, and Ps3, without affecting bacterial viability. In addition, CFP, CFPF, and CFPC significantly reduced the expression of lasI and rhlI genes. The molecular docking analysis elucidated that the QS inhibitory effect was possibly caused by the interaction with QS receptors. Both CFPF and CFPC interacted strongly with LasI, LasR and PqsR receptors with a much high ICM scores compared to CFP that could be the cause of elimination of natural ligand binding. Therefore, CFPC and CFPF are potent inhibitors of quorum sensing signaling and virulence factors of P. aeruginosa.

Molecular Mechanisms and Applications of N-Acyl Homoserine Lactone-Mediated Quorum Sensing in Bacteria

“…The LuxI enzyme produces the QS signal molecule (the N-3-oxo-hexanoyl-homoserine lactone), and LuxR is a transcription regulator that binds to the AHL signal and regulates bioluminescence via the luxCDABEG operon [ 9 ]. Following the discovery of the AHL-QS system, researchers discovered that AHL-QS is prevalent in a wide range of Proteobacteria and influences vital characteristics such as motility [ 10 ], pigment production [ 11 ], and biofilm formation [ 12 ]. Our molecular understanding of the QS system has been useful in studying plant–microbe, animal–microbe, and human–microbe interactions.…”

Comparison of different ratios of cefoperazone/sulbactam in patients with pyelonephritis

“…11 Cefoperazone sodium is a long-acting cephalosporin with a strong antibacterial effect on a variety of Gram-negative aerobic and anaerobic bacteria, but it has poor resistance to β-lactamases produced by various bacteria, such as Enterococcus and Pseudomonas aeruginosa. 15 A study by Kuo et al 16 showed that sulbactam sodium can significantly enhance the antibacterial 17 also demonstrated that a stepwise increase in the ratio of sulbactam to partner β-lactam antibiotics led to a stepwise decrease in the minimum inhibitory concentrations (MICs) and a stepwise increase in the susceptibility rates. Ratio 1:3 of cefoperazone/ sulbactam resulted in 91% sensitivity rate of Acinetobacter Baumannii.…”

The Molecular Architecture of Pseudomonas aeruginosa Quorum-Sensing Inhibitors

“…Cefoperazone (CFP, Figure 15 b) is one of the most widely used β-lactam antibiotics. Some researchers tried to explore some other activities of CFP, and its metallic derivatives cefoperazone iron complex (CFPF) and cefoperazone cobalt complex (CFPC) were found to interact more strongly with LasI, LasR, and PqsR receptors than CFP, CFPF, and CFPC and to eliminated QS-associated virulence factors [ 115 ]. Hadizadeh et al found that oxicams (piroxicam and meloxicam, Figure 15 b) can serve as the best inhibitors of LasR from the studied nonsteroidal anti-inflammatory drug (NSAID) compounds and also have potential antagonist activity against PqsE in the pqs system [ 116 ].…”