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Among the mechanisms involved, efflux pumps stand out, reducing the intracellular concentration of drugs and contributing to multidrug resistance. In this context, inhibitors of these pumps emerge as a promising approach, as they increase the intracellular concentration of antibiotics. Natural compounds, such as the triterpene lupeol, have been investigated as potential modulators of bacterial resistance due to their relevant biological activities. This study evaluated, from a mechanistic perspective, the ability of lupeol to inhibit the MepA efflux pump in the K2068 strain of\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    . The minimum inhibitory concentration (MIC) was determined, efflux inhibition assays were performed, membrane permeability analysis was conducted using Sytox Green, ethidium bromide fluorescence was evaluated, RT-qPCR was performed, and molecular docking was performed. The results demonstrated that lupeol exhibits isolated antibacterial activity considered without clinical relevance (MIC\u2009\u2265\u20091024\u00a0\u00b5g\/mL); however, it reduced the MIC of ciprofloxacin and ethidium bromide, indicating inhibition of the MepA pump. No alteration in membrane permeability and an increase in ethidium bromide fluorescence were observed with increasing lupeol concentration. RT-qPCR showed inhibition of\n                    <jats:italic>mepA<\/jats:italic>\n                    gene expression. In molecular docking, the compound presented a binding energy of\u2009\u2212\u20099.01\u00a0kcal\/mol, with van der Waals, hydrophobic, and hydrogen bonding interactions. It is concluded that lupeol shows potential as an efflux pump inhibitor, acting on the functional inhibition of the pump and the negative regulation of mepA gene expression, thus configuring itself as an adjuvant strategy in combating bacterial resistance.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05342-5","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T04:14:34Z","timestamp":1778040874000},"page":"16005-16014","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lupeol as a modulator of bacterial resistance mediated by the MepA efflux pump in Staphylococcus aureus"],"prefix":"10.1007","volume":"399","author":[{"given":"Nara Juliana Santos","family":"Ara\u00fajo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila Aparecida Pereira","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cicera Datiane Morais","family":"Oliveira-Tintino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Gon\u00e7alves","family":"Alencar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"do Socorro Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Raquel Pereira","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliete Bezerra","family":"Soares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana\u00edna Esmeraldo","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saulo Relison","family":"Tintino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Lima-Bezerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrique Douglas Melo","family":"Coutinho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Leopoldino Coelho","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Maria","family":"Barbosa-Filho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Bezerra","family":"de Ara\u00fajo-Neto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Carolina Ferreira","family":"Araujo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Arthur","family":"de Oliveira Borges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gild\u00eania Alves","family":"de Ara\u00fajo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Thy\u00e1lisson","family":"da Costa Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline Cosmo","family":"Andrade-Pinheiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"5342_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2025.e42899","author":"F Aflakian","year":"2025","unstructured":"Aflakian F, Hashemitabar G (2025) Biosynthesized silver nanoparticles at subinhibitory concentrations as inhibitors of quorum sensing, pathogenicity, and biofilm formation in Pseudomonas aeruginosa PAO1. 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