Celecoxib potentiates antibiotic uptake by altering membrane potential and permeability in Staphylococcus aureus

Abstract Background We have shown previously that celecoxib enhances the antibacterial effect of antibiotics and has sensitized drug-resistant bacteria to antibiotics at low concentrations using in vitro and in vivo model systems and also using clinically isolated ESKAPE pathogens. Objectives To identify the mechanism of action of celecoxib in potentiating the effect of antibiotics on bacteria. Methods Toxicogenomic expression analysis of Staphylococcus aureus in the presence or absence of ampicillin, celecoxib or both was carried out by microarray followed by validation of microarray results by flow cytometry and real-time PCR analysis, cocrystal development and analysis. Results The RNA expression map clearly indicated a change in the global transcriptome of S. aureus in the presence of cells treated with ampicillin alone, which was similar to that of celecoxib-treated cells in co-treated cells. Several essential, non-essential and virulence genes such as α-haemolysin (HLA), enterotoxins and β-lactamase were differentially regulated in co-treated cells. Further detailed analysis of the expression data indicated that the ion transporters and enzymes of the lipid biosynthesis pathway were down-regulated in co-treated cells leading to decreased membrane permeability and membrane potential. Cocrystal studies using Powder-X-Ray Diffraction (PXRD) and differential scanning calorimetry (DSC) indicated interactions between celecoxib and ampicillin, which might help in the entry of antibiotics. Conclusions Although further studies are warranted, here we report that celecoxib alters membrane potential and permeability, specifically by affecting the Na+/K+ ion transporter, and thereby increases the uptake of ampicillin by S. aureus.