A systematic review and computational analysis of bioactive compounds from Nigella sativa against methicillin-resistant Staphylococcus aureus (MRSA)

MRSA is a major cause of antibiotic-resistant infections worldwide. The increasing limitations of currently available treatment options have prompted interest in plant-derived antimicrobial agents. A systematic review was conducted in accordance with the PRISMA 2020 guidelines using the PubMed, Web of Science, and Scopus databases. Methodological quality was assessed using a modified OHAT risk-of-bias tool, independently applied by two reviewers. Additionally, molecular docking, MD simulation, and ADMET analyses were performed to investigate the interactions between four major Nigella sativa (NS) phytochemicals (thymoquinone, carvacrol, p-cymene, and trans-anethol) and penicillin-binding protein 2a (PBP2a), the key resistance protein in MRSA. Ceftaroline fosamil was used as the reference drug. Fourteen in vitro studies met the inclusion criteria. Reported minimum inhibitory concentration values ranged from < 0.25 to 6400 µg/mL, with organic solvent and cold-pressed extracts generally exhibiting greater antibacterial activity than aqueous preparations. Three studies reported synergistic effects between NS and β-lactam antibiotics. Molecular docking showed that carvacrol (− 7.1 kcal/mol) and TQ (− 6.7 kcal/mol) displayed stronger binding affinities toward PBP2a than p -cymene and trans-anethole. MD simulations demonstrated stable protein–ligand interactions, while ADMET analysis indicates favourable pharmacokinetic profiles for thymoquinone and carvacrol, and toxicity for p-cymene and trans-anethol. The integrated findings support a proposed cooperative anti-MRSA mechanism in which TQ and carvacrol may interact with PBP2a. At the same time, p-cymene and trans-anethole enhance antibacterial activity through membrane-associated effects. These findings provide a basis for further standardized in vitro and in vivo studies to validate the therapeutic potential of NS-derived compounds against MRSA.