{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T12:44:43Z","timestamp":1784033083130,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry &amp;amp; Biodiversity"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Antibiotic resistance poses a serious challenge to public health, particularly in the case of\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    , a Gram\u2010positive bacterium that employs multiple resistance mechanisms, including efflux pumps such as NorA, which extrude antimicrobial compounds from the cell and reduce antibiotic efficacy. Therefore, the search for substances capable of inhibiting these mechanisms represents a promising strategy to combat bacterial resistance. Betulinic acid (BA), a pentacyclic triterpene of the lupane type, commonly found in different parts of plants, has demonstrated various pharmacological activities, including antibacterial effects. This study investigated, through in vitro and in silico analyses, the inhibitory action of BA on the NorA efflux pump in\n                    <jats:italic>S. aureus<\/jats:italic>\n                    strains SA\u20101199 and SA\u20101199B. The minimum inhibitory concentrations (MICs) were determined using the broth microdilution method. Subsequently, their effects on efflux pump\u2010mediated antibiotic resistance were evaluated by reducing the MIC of the antibiotic and ethidium bromide (EtBr), while fluorimetry and permeability potential tests were carried out using the SYTOX Green fluorescence method. Although BA did not show intrinsic antibacterial activity, showing MIC \u2265 1024\u00a0\u00b5g\/mL, it was able to decrease the MIC of norfloxacin and EtBr, as well as influence membrane permeability and increase fluorescence emission. The results, therefore, indicate that BA has considerable potential as an efflux pump inhibitor and could help in the treatment of resistant bacterial infections.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202502869","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:05:19Z","timestamp":1765994719000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Action of Betulinic Acid in the Inhibition of Efflux Pump NorA in\n                    <i>Staphylococcus aureus<\/i>\n                    Strains: In Vitro and In Silico Approaches"],"prefix":"10.1002","volume":"23","author":[{"given":"Camila Aparecida Pereira","family":"da Silva","sequence":"first","affiliation":[{"name":"Graduate Program in Health Sciences Federal University of Cariri  Barbalha Brazil"},{"name":"Laboratory of Applied Microbiology\u2013LAMAP Federal University of Cariri  Barbalha Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nara juliana","family":"Santos Araujo","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Microbiology\u2013LAMAP Federal University of Cariri  Barbalha Brazil"},{"name":"Multicenter Postgraduate Program in Biochemistry and Molecular Biology Federal University of Cariri  Barbalha Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00edcera Datiane Morais","family":"Oliveira\u2010Tintino","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology Regional University of Cariri \u2013 LMBM  Crato Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Maria Barbosa","family":"Filho","sequence":"additional","affiliation":[{"name":"Federal University of Paraiba \u2013 UFPB  Jo\u00e3o Pessoa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Gon\u00e7alves","family":"Alencar","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology Regional University of Cariri \u2013 LMBM  Crato Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Bezerra","family":"de Ara\u00fajo\u2010Neto","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences, Biosciences Center Federal University of Pernambuco  Recife Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefa Sayonara","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Multicenter Postgraduate Program in Biochemistry and Molecular Biology Federal University of Cariri  Barbalha Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliete Bezerra","family":"Soares","sequence":"additional","affiliation":[{"name":"Multicenter Postgraduate Program in Biochemistry and Molecular Biology Federal University of Cariri  Barbalha Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina Bandeira","family":"Domiciano","sequence":"additional","affiliation":[{"name":"Federal University of Paraiba \u2013 UFPB  Jo\u00e3o Pessoa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6634-4207","authenticated-orcid":false,"given":"Henrique Douglas Melo","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology Regional University of Cariri \u2013 LMBM  Crato Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline Cosmo","family":"Andrade\u2010Pinheiro","sequence":"additional","affiliation":[{"name":"Graduate Program in Health Sciences Federal University of Cariri  Barbalha Brazil"},{"name":"Laboratory of Applied Microbiology\u2013LAMAP Federal University of Cariri  Barbalha Brazil"},{"name":"Multicenter Postgraduate Program in Biochemistry and Molecular Biology Federal University of Cariri  Barbalha Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(21)02724\u20100"},{"key":"e_1_2_10_3_1","unstructured":"G. B.BritoandM.Trevisan \u201cThe Misuse of Antibiotics and the Imminent Risk of Bacterial Resistance \u201dRevista Artigos.Com30(2021):e7902 https:\/\/acervomais.com.br\/index.php\/artigos\/article\/view\/7902. ISSN 2596\u20100253."},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1130562"},{"key":"e_1_2_10_5_1","unstructured":"C. D. M. O.Oliveira\u2010Tintino Evaluation of Antibacterial and Efflux Pump Inhibitory Activity in Staphylococcus aureus Strains by Sulfonamide 1 8\u2010Naphthyridines: An In Vitro and In Silico Approach(PhD thesis Federal University of Pernambuco Center for Biosciences 2021)."},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579\u2010023\u201000852\u2010y"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2023.117187"},{"key":"e_1_2_10_8_1","volume-title":"WHO Publishes List of Bacteria for Which New Antibiotics Are Urgently Needed","author":"Pan American Health Organization","year":"2017"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010022\u201000994\u20109"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12060965"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2023.105925"},{"key":"e_1_2_10_12_1","unstructured":"D. F.Rodrigues Modulation of Drug Resistance by Furocoumarins and Furochromones in Staphylococcus aureus(master's thesis Universidade Federal da Para\u00edba 2022)."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04876\u201022"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens12030449"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115788"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11101\u2010018\u20109564\u20102"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2022.154012"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26041081"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph16081180"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12906\u2010019\u20102512\u2010x"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9091104"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0256364"},{"key":"e_1_2_10_23_1","volume-title":"Performance Standards for Antimicrobial Susceptibility Testing. CLSI Document M100","author":"Clinical and Laboratory Standards Institute","year":"2020"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2025.109572"},{"key":"e_1_2_10_25_1","unstructured":"G. W. P.Sales.Evaluation of the Antimicrobial Activity and Mechanism of Action of the Essential Oil Extracted From the Peel of Fruits of Hymenaea courbaril L. (master's thesis Federal University of Cear\u00e1 2014)."},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28041819"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/BIOM13030466"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky427"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2008.09.001"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.22271\/plants.2024.v12.i1a.1625"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.46602\/jcsn.v45i4.492"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiac.2022.01.003"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00840\u201016"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/open.202500227"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116625"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodcont.2021.108488"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2021.1976277"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S113556"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sajb.2022.03.020"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.0c00983"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11101287"}],"container-title":["Chemistry &amp; Biodiversity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbdv.202502869","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbdv.202502869","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbdv.202502869","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T06:35:01Z","timestamp":1775889301000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cbdv.202502869"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":41,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/cbdv.202502869"],"URL":"https:\/\/doi.org\/10.1002\/cbdv.202502869","archive":["Portico"],"relation":{},"ISSN":["1612-1872","1612-1880"],"issn-type":[{"value":"1612-1872","type":"print"},{"value":"1612-1880","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]},"assertion":[{"value":"2025-08-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02869"}}