Restoring Penicillin Activity Against Resistant Staphylococcus aureus Through Multi‐Target Inhibition by Endemic Hypericum aegyptiacum subsp.

ABSTRACT

The emergence of penicillin‐resistant Staphylococcus aureus poses a significant challenge to antimicrobial therapy. Natural products may provide resistance‐modifying agents (RMAs) capable of restoring antibiotic activity. Here, the essential oil (EO) of the endemic plant Hypericum aegyptiacum subsp. maroccanum (HAEM), collected from the Moghrar region (Naâma Province, Algeria), was investigated for its ability to enhance penicillin G activity against resistant S. aureus . GC‐FID and GC‐MS analyses identified 35 compounds, accounting for 99.92% of the total oil, with α‐pinene (50.7%), β‐pinene (19.11%), and (+)‐m‐mentha‐1(6),8‐diene (9.42%) as major constituents. HAEM EO combined with penicillin G restored antibacterial activity against penicillin‐resistant S. aureus SCS03, with the strongest synergistic effect observed at 8.40 µg/mL penicillin G and 61.33 µg/mL EO. To explore possible mechanisms underlying this restored activity, molecular docking was performed against β‐lactamase (PDB: 1PIO) and PBP2a (PDB: 6H5O). Several HAEM EO constituents, including oxido‐5,17‐α‐copaen‐11‐ol, calarene, cadinene, and α‐maaliene, exhibited strong predicted binding affinities and favorable predicted bioavailability and low toxicity profiles. These findings suggest that HAEM EO may constitute a promising source of resistance‐modifying compounds, although further experimental validation is warranted.