Lupeol as a Potential Inhibitor of NorA Efflux Pumps in Staphylococcus aureus: In Silico and In Vitro Evidence

Antimicrobial resistance remains one of the major challenges to global public health, compromising the effectiveness of treatments and contributing to increased morbidity and mortality associated with bacterial infections. Among the mechanisms involved, efflux pumps—such as NorA, expressed in resistant strains of Staphylococcus aureus—are particularly noteworthy. These transport proteins actively expel antibiotics from the cell, reducing their intracellular concentration. In this context, natural compounds have been explored as potential resistance inhibitors, with a focus on the triterpene lupeol, known for its pharmacological properties. This study evaluates the activity of lupeol against the NorA efflux pump using in vitro assays and in silico modeling. The minimum inhibitory concentration (MIC) is determined by broth microdilution, and pump inhibition is assessed via ethidium bromide-induced fluorescence. SYTOX Green assays indicated that lupeol does not compromise bacterial membrane integrity. Although lupeol presented a MIC ≥ 1024 μg mL⁻¹, it demonstrates significant inhibition of NorA activity. Molecular docking reveals a binding energy of –7.112 kcal mol⁻¹ and interactions with key residues of the protein, outperforming the CCCP control. These findings suggest that lupeol acts as a modulator of bacterial resistance, with potential application as a therapeutic adjuvant in the treatment of infections caused by multidrug-resistant S. aureus.

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