Abstract
Development of drug resistance in opportunistic pathogens is one of the major healthcare challenges associated with infection management. Combination therapy has many advantages due to the simultaneous action of two drugs on two separate cellular targets. However, selection of the drugs should offer safety and synergistic interaction against most of the strains. Here, the efficacy of antibiotics in combination with quercetin, a natural flavonoid capable of targeting quorum sensing was tested against biofilm-forming Pseudomonas aeruginosa strains previously isolated from catheter associated urinary tract infection. Based on the antibiotic susceptibility pattern, synergistic effect of quercetin with selected antibiotics (levofloxacin, ceftriaxone, gentamycin, tobramycin and amikacin) was tested at the fractional concentrations of MIC by the checkerboard method and the fractional inhibitory concentration index (FICi) was calculated to estimate the synergistic effect. Effect of the synergistic combinations were further tested using time-kill assay, and against biofilm formation and biofilm cell viability. Cytotoxicity assays were performed using Human Embryonic Kidney 293T cells (HEK-293T) using the effective drug combinations with respective controls. The biofilm formation and biofilm cell viability were drastically affected with quercetin and selected antibiotics combinations with ≥80% inhibition. In vitro infection studies showed that all the strains could exert significant cell killing (68 to 85%) and the drug combinations decreased the infection rate significantly by reducing the cell killing effect of P. aeruginosa (p<0.05). The synergistic effect of quercetin is attributed to its quorum sensing inhibitory properties. These findings indicate that quercetin along with existing antibiotics can potentiate the treatment against P. aeruginosa infection and may reduce the selection pressure due to antibiotic overuse.
Highlights
Resistance to antibiotics among the biofilm-forming Pseudomonas aeruginosa (P. aeruginosa) depict a formidable challenge to the healthcare sector
In P. aeruginosa strains treated with quercetin a significant decrease in the quorum sensing controlled virulence factors such as rhamnolipid production and swarming motility were observed (S1A and S1B Fig)
The antibiotic with quercetin combinations against P. aeruginosa strains isolated from the catheter associated urinary tract infection showed encouraging results
Summary
Resistance to antibiotics among the biofilm-forming Pseudomonas aeruginosa (P. aeruginosa) depict a formidable challenge to the healthcare sector. Quercetin and antibiotic combinations against P. aeruginosa aeruginosa complicates treatment of various conditions ranging from the non-healing of skin wounds to chronic respiratory conditions. Expansion of antibiotic use facilitating the influx of antibiotic traces into the environment has contributed to the high rates of antibiotic resistance [1,2,3]. The global changes in gene expression, enhancing virulence, and the acquisition of antibiotic resistance occurs due to the protection of the bacteria within the biofilm architecture [4]. In P. aeruginosa, quorum sensing is a predominant phenomenon regulating many virulence factors including biofilm formation [5]
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