Integrated In silico and In Vitro Evaluation of Piperine Derivatives as Potential Efflux Pump Inhibitors in Methicillin-Resistant Staphylococcus aureus

Abstract

Abstract The increasing prevalence of antibiotic resistance mediated by efflux pump activity represents a major challenge in the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Efflux pumps such as NorA and MepA reduce intracellular antibiotic accumulation and contribute significantly to decreased antibiotic efficacy. In this study, PBSA-7, a piperine-derived compound, was evaluated as a potential efflux pump inhibitor using an integrated in silico and in vitro approach. Computational analysis, including molecular docking, molecular dynamics simulations, Lipinski rule assessment, and ADMET prediction, was performed to investigate the interaction profiles and drug-likeness of the compound. PBSA-7 demonstrated favorable binding affinities toward NorA (−9.3 kcal/mol) and MepA (−9.0 kcal/mol), with stable interaction patterns observed during the molecular dynamics simulations. ADMET predictions suggested generally acceptable pharmacokinetic properties, although relatively high lipophilicity may require further structural optimization. Functional evaluation was performed by using checkerboard combination assays and ethidium bromide accumulation experiments. In the checkerboard assay, PBSA-7 reduced bacterial growth when combined with ciprofloxacin compared to the antibiotic alone, suggesting that the compound may enhance the antibacterial activity of ciprofloxacin against MRSA under the tested conditions. Ethidium bromide accumulation assays showed increased intracellular fluorescence, indicating potential interference with bacterial efflux pump activity. Taken together, these findings suggest that PBSA-7 may act as a potential efflux pump inhibitor associated with NorA- and MepA-mediated resistance mechanisms in MRSA, highlighting its possible role as an antibiotic adjuvant. However, further experimental studies are required to confirm the underlying mechanism and evaluate its therapeutic potential.

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