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Thymoquinone (TQ) has evidently demonstrated multiple activities, antibacterial being the most effective. Knowledge about TQ activity against multidrug-resistant <jats:italic>Staphylococcus aureus<\/jats:italic> is very scarce. Therefore, the present study was conducted to investigate TQ resistance modulation in ciprofloxacin (CIP) and doxycycline (DO) multidrug-resistant <jats:italic>S. aureus<\/jats:italic>. Forty-seven samples were collected from different sources, and <jats:italic>S. aureus<\/jats:italic> was isolated and identified. Then, <jats:italic>S. aureus<\/jats:italic> resistance profiles to antimicrobials, <jats:italic>N. sativa<\/jats:italic> essential oil, and TQ; the correlation between TQ-MIC readings and disc diffusion; cartwheel and ethidium bromide (EtBr) accumulation assays; and <jats:italic>norA<\/jats:italic> gene expression were all described within silico molecular docking for TQ interactions with norA efflux pump protein. TQ-MICs ranged from 5\u2013320\u00a0\u00b5g\/ml. TQ down-regulated <jats:italic>norA<\/jats:italic> gene expression, resulting in a drop in efflux pump activity of 77.5\u201390.6% in the examined strains, comparable to that observed with verapamil. Exposure of <jats:italic>S. aureus<\/jats:italic> strains to CIP and DO raises the initial basal efflux pumping expression to 34.2 and 22.9 times, respectively. This induced efflux pumping overexpression was substantially reduced by 97.7% when TQ was combined with CIP or DO. There was a significant reduction of MICs of CIP and DO MICs by 2\u201315 and 2\u20134 folds, respectively, after treatment with 0.5XMIC-TQ in resistance modulation assays. These results refer to TQ ligand inhibitory interactions with NorA protein in molecular docking. Interpretations of inhibition zone diameters (IZDs) of disc diffusion and TQ-MICs exhibit independence of MICs from IZDs, as indicated by invalid linear regression analysis. TQ significantly reduced efflux pumping <jats:italic>S. aureus<\/jats:italic> induced by CIP and DO, but further investigations are needed to improve TQ-pharmacokinetics to restore CIP and DO activity and suppress fluoroquinolone and doxycycline-resistant <jats:italic>S. aureus<\/jats:italic> selection in clinical and animal settings.<\/jats:p>","DOI":"10.1038\/s41598-024-65991-5","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T03:31:49Z","timestamp":1721187109000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Thymoquinone\u2019 potent impairment of multidrug-resistant Staphylococcus aureus NorA efflux pump activity"],"prefix":"10.1038","volume":"14","author":[{"given":"Adel Attia M.","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Y.","family":"Abdelgalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek","family":"Khamis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashraf M. 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