{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:06:03Z","timestamp":1790960763863,"version":"4.1.0"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T00:00:00Z","timestamp":1707523200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T00:00:00Z","timestamp":1707523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Microbiol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p><jats:italic>Candida albicans<\/jats:italic> is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in <jats:italic>C. albicans<\/jats:italic>. New treatment approaches are needed to combat candidiasis especially in the dwindled supply of new effective and safe antifungals. The resistance to azoles is mainly attributed to export of azoles outside the cells by means of the efflux pump that confers cross resistance to all azoles including fluconazole (FLC).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Objectives<\/jats:title>\n                <jats:p>This study aimed to investigate the possible efflux pump inhibiting activity of fusidic acid (FA) in <jats:italic>C. albicans<\/jats:italic> resistant isolates and the potential use of Fusidic acid in combination with fluconazole\u00a0to potentiate the antifungal activity of\u00a0fluconazole to restore its activity in the resistant <jats:italic>C. albicans<\/jats:italic> isolates.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The resistance of <jats:italic>C. albicans<\/jats:italic> isolates was assessed by determination of minimum inhibitory concentration. The effect of Fusidic acid at sub-inhibitory concentration on efflux activity was assayed by rhodamine 6G efflux assay and intracellular accumulation. Mice model studies were conducted to evaluate the anti-efflux activity of Fusidic acid and its synergistic effects in combination with fluconazole. Impact of Fusidic acid on ergosterol biosynthesis was quantified. The synergy of fluconazole when combined with Fusidic acid was investigated by determination of minimum inhibitory concentration. The cytotoxicity of Fusidic acid was tested against erythrocytes. The effect of Fusidic acid on efflux pumps was tested at the molecular level by real-time PCR and in silico study. In vivo vulvovaginitis mice model was used to confirm the activity of the combination in treating vulvovaginal candidiasis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Fusidic acid showed efflux inhibiting activity as it increased the accumulation of rhodamine 6G, a substrate for ABC-efflux transporter, and decreased its efflux in <jats:italic>C. albicans<\/jats:italic> cells. The antifungal activity of fluconazole was synergized when combined with Fusidic acid. Fusidic acid exerted only minimal cytotoxicity on human erythrocytes indicating its safety. The FA efflux inhibitory activity could be owed to its ability to interfere with efflux protein transporters as revealed by docking studies and downregulation of the efflux-encoding genes of both ABC transporters and MFS superfamily. Moreover, in vivo mice model showed that using fluconazole-fusidic acid combination by vaginal route enhanced fluconazole antifungal activity as shown by lowered fungal burden and a negligible histopathological change in vaginal tissue.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The current findings highlight FA\u2019s potential as a potential adjuvant to FLC in the treatment of vulvovaginal candidiasis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12866-024-03181-z","type":"journal-article","created":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T08:02:23Z","timestamp":1707552143000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model"],"prefix":"10.1186","volume":"24","author":[{"given":"Salwa E.","family":"Gomaa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisham A.","family":"Abbas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma A.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A. M.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek M.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyaa S.","family":"Abdel Halim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mashael A.","family":"Alghamdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basem","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anis Ahmad","family":"Chaudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Elkelish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fehmi","family":"Boufahja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wael A. H.","family":"Hegazy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma Al-zahraa A.","family":"Yehia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,10]]},"reference":[{"issue":"3","key":"3181_CR1","doi-asserted-by":"publisher","first-page":"115509","DOI":"10.1016\/j.diagmicrobio.2021.115509","volume":"101","author":"A D\u00edez","year":"2021","unstructured":"D\u00edez A, Carrano G, Breg\u00f3n-Villahoz M, Cu\u00e9tara M-S, Garc\u00eda-Ruiz JC, Fernandez-de-Larrinoa I, Moragues M-D. Biomarkers for the diagnosis of invasive candidiasis in immunocompetent and immunocompromised patients. Diagn Microbiol Infect Dis. 2021;101(3):115509.","journal-title":"Diagn Microbiol Infect Dis"},{"key":"3181_CR2","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1038\/nrdp.2018.26","volume":"4","author":"PG Pappas","year":"2018","unstructured":"Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ. Invasive candidiasis. Nat Rev Dis Prim. 2018;4:18026.","journal-title":"Nat Rev Dis Prim"},{"issue":"11","key":"3181_CR3","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1001\/jama.291.11.1368","volume":"291","author":"MR Anderson","year":"2004","unstructured":"Anderson MR, Klink K, Cohrssen A. Evaluation of vaginal complaints. JAMA. 2004;291(11):1368\u201379.","journal-title":"JAMA"},{"issue":"4","key":"3181_CR4","doi-asserted-by":"publisher","first-page":"267","DOI":"10.3390\/jof6040267","volume":"6","author":"V Sustr","year":"2020","unstructured":"Sustr V, Foessleitner P, Kiss H, Farr A. Vulvovaginal candidosis: Current concepts, challenges and perspectives. J Fungi. 2020;6(4):267.","journal-title":"J Fungi"},{"issue":"1","key":"3181_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12934-020-01390-5","volume":"19","author":"PR De Gregorio","year":"2020","unstructured":"De Gregorio PR, Parolin C, Abruzzo A, Luppi B, Protti M, Mercolini L, Silva JA, Giordani B, Marangoni A, Nader-Mac\u00edas MEF. Biosurfactant from vaginal Lactobacillus crispatus BC1 as a promising agent to interfere with Candida adhesion. Microb Cell Fact. 2020;19(1):1\u201316.","journal-title":"Microb Cell Fact"},{"issue":"4","key":"3181_CR6","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/cid\/civ933","volume":"62","author":"PG Pappas","year":"2016","unstructured":"Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1\u201350.","journal-title":"Clin Infect Dis"},{"issue":"8","key":"3181_CR7","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.3390\/pharmaceutics14081646","volume":"14","author":"SM Alshahrani","year":"2022","unstructured":"Alshahrani SM, Khafagy ES, Riadi Y, Al Saqr A, Alfadhel MM, Hegazy WAH. Amphotericin B-PEG conjugates of ZnO nanoparticles: enhancement antifungal activity with minimal toxicity. Pharmaceutics. 2022;14(8):1646.","journal-title":"Pharmaceutics"},{"issue":"6","key":"3181_CR8","doi-asserted-by":"publisher","first-page":"312","DOI":"10.3390\/antibiotics9060312","volume":"9","author":"S Bhattacharya","year":"2020","unstructured":"Bhattacharya S, Sae-Tia S, Fries BC. Candidiasis and mechanisms of antifungal resistance. Antibiotics. 2020;9(6):312.","journal-title":"Antibiotics"},{"issue":"15","key":"3181_CR9","doi-asserted-by":"publisher","first-page":"6847","DOI":"10.3390\/app11156847","volume":"11","author":"AN Khayyat","year":"2021","unstructured":"Khayyat AN, Abbas HA, Mohamed MFA, Asfour HZ, Khayat MT, Ibrahim TS, Youns M, Khafagy E-S, Abu Lila AS, Safo MK, Hegazy WA. Not only antimicrobial: metronidazole mitigates the virulence of proteus mirabilis Isolated from macerated diabetic foot ulcer. Appl Sci. 2021;11(15):6847.","journal-title":"Appl Sci"},{"issue":"1","key":"3181_CR10","doi-asserted-by":"publisher","first-page":"148","DOI":"10.3390\/life13010148","volume":"13","author":"ASA Lila","year":"2023","unstructured":"Lila ASA, Rajab AA, Abdallah MH, Rizvi SMD, Moin A, Khafagy E-S, Tabrez S, Hegazy WA. Biofilm lifestyle in recurrent urinary tract infections. Life. 2023;13(1):148.","journal-title":"Life"},{"key":"3181_CR11","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.3389\/fmicb.2016.02173","volume":"7","author":"SG Whaley","year":"2017","unstructured":"Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS, Rogers PD. Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species. Front Microbiol. 2017;7:2173.","journal-title":"Front Microbiol"},{"issue":"6","key":"3181_CR12","doi-asserted-by":"publisher","first-page":"680","DOI":"10.4239\/wjd.v14.i6.680","volume":"14","author":"AA Rajab","year":"2023","unstructured":"Rajab AA, Hegazy WA. What\u2019s old is new again: Insights into diabetic foot microbiome. World J Diabetes. 2023;14(6):680\u2013704.","journal-title":"World J Diabetes"},{"issue":"6","key":"3181_CR13","doi-asserted-by":"publisher","first-page":"3390","DOI":"10.1021\/acs.chemrev.0c00199","volume":"121","author":"Y Lee","year":"2021","unstructured":"Lee Y, Puumala E, Robbins N, Cowen LE. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem Rev. 2021;121(6):3390\u2013411.","journal-title":"Chem Rev"},{"issue":"10","key":"3181_CR14","doi-asserted-by":"publisher","first-page":"2676","DOI":"10.1128\/AAC.45.10.2676-2684.2001","volume":"45","author":"S Perea","year":"2001","unstructured":"Perea S, L\u00f3pez-Ribot JL, Kirkpatrick WR, McAtee RK, Santill\u00e1n RA, Mart\u0131\u0301nez M, Calabrese D, Sanglard D, Patterson TF. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2001;45(10):2676\u201384.","journal-title":"Antimicrob Agents Chemother"},{"issue":"6","key":"3181_CR15","doi-asserted-by":"publisher","first-page":"984","DOI":"10.3109\/13880209.2015.1091483","volume":"54","author":"J Shao","year":"2016","unstructured":"Shao J, Zhang M, Wang T, Li Y, Wang C. The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans. Pharm Biol. 2016;54(6):984\u201392.","journal-title":"Pharm Biol"},{"issue":"5","key":"3181_CR16","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.ijantimicag.2013.12.009","volume":"43","author":"S Liu","year":"2014","unstructured":"Liu S, Hou Y, Chen X, Gao Y, Li H, Sun S. Combination of fluconazole with non-antifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery. Int J Antimicrob Agents. 2014;43(5):395\u2013402.","journal-title":"Int J Antimicrob Agents"},{"issue":"5","key":"3181_CR17","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.3390\/biomedicines10051169","volume":"10","author":"MT Khayat","year":"2022","unstructured":"Khayat MT, Abbas HA, Ibrahim TS, Khayyat AN, Alharbi M, Darwish KM, Elhady SS, Khafagy E-S, Safo MK, Hegazy WAH. Anti-quorum sensing activities of gliptins against Pseudomonas aeruginosa and Staphylococcus aureus. Biomedicines. 2022;10(5):1169.","journal-title":"Biomedicines"},{"issue":"4","key":"3181_CR18","doi-asserted-by":"publisher","first-page":"465","DOI":"10.3390\/antibiotics11040465","volume":"11","author":"WAH Hegazy","year":"2022","unstructured":"Hegazy WAH, Salem IM, Alotaibi HF, Khafagy E-S, Ibrahim D. Terazosin interferes with quorum sensing and type three secretion system and diminishes the bacterial espionage to mitigate the Salmonella typhimurium pathogenesis. Antibiotics. 2022;11(4):465.","journal-title":"Antibiotics"},{"key":"3181_CR19","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3389\/fmicb.2019.00041","volume":"10","author":"A Mir\u00f3-Canturri","year":"2019","unstructured":"Mir\u00f3-Canturri A, Ayerbe-Algaba R, Smani Y. Drug repurposing for the treatment of bacterial and fungal infections. Front Microbiol. 2019;10:41.","journal-title":"Front Microbiol"},{"issue":"1","key":"3181_CR20","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1080\/21505594.2020.1868814","volume":"12","author":"Y Vega-Chac\u00f3n","year":"2021","unstructured":"Vega-Chac\u00f3n Y, de Albuquerque MC, Pavarina AC, Goldman GH. Mima EGdO: Verapamil inhibits efflux pumps in Candida albicans, exhibits synergism with fluconazole, and increases survival of Galleria mellonella. Virulence. 2021;12(1):231\u201343.","journal-title":"Virulence"},{"issue":"12","key":"3181_CR21","doi-asserted-by":"publisher","first-page":"3366","DOI":"10.1128\/AAC.45.12.3366-3374.2001","volume":"45","author":"K Nakamura","year":"2001","unstructured":"Nakamura K, Niimi M, Niimi K, Holmes AR, Yates JE, Decottignies A, Monk BC, Goffeau A, Cannon RD. Functional expression of Candida albicans drug efflux pump Cdr1p in a Saccharomyces cerevisiae strain deficient in membrane transporters. Antimicrob Agents Chemother. 2001;45(12):3366\u201374.","journal-title":"Antimicrob Agents Chemother"},{"key":"3181_CR22","doi-asserted-by":"publisher","unstructured":"Lamping E, Madani G, Lee HJ, Niimi M, Cannon RD. Structure\u2013Function Analyses of Multidrug Transporters. In: Prasad R, editor. Candida albicans: Cellular and Molecular Biology. Cham:\u00a0Springer; 2017. https:\/\/doi.org\/10.1007\/978-3-319-50409-4_18.","DOI":"10.1007\/978-3-319-50409-4_18"},{"issue":"8","key":"3181_CR23","doi-asserted-by":"publisher","first-page":"e0203079","DOI":"10.1371\/journal.pone.0203079","volume":"13","author":"S Singh","year":"2018","unstructured":"Singh S, Fatima Z, Ahmad K, Hameed S. Fungicidal action of geraniol against Candida albicans is potentiated by abrogated CaCdr1p drug efflux and fluconazole synergism. PLoS One. 2018;13(8):e0203079.","journal-title":"PLoS One"},{"issue":"3","key":"3181_CR24","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.jsps.2022.01.011","volume":"30","author":"AM El-Ganiny","year":"2022","unstructured":"El-Ganiny AM, Kamel HA, Yossef NE, Mansour B, El-Baz AM. Repurposing pantoprazole and haloperidol as efflux pump inhibitors in azole resistant clinical Candida albicans and non-albicans isolates. Saudi Pharm J. 2022;30(3):245\u201355.","journal-title":"Saudi Pharm J"},{"key":"3181_CR25","first-page":"11","volume":"2018","author":"P-P Wu","year":"1945","unstructured":"Wu P-P, He H, Hong WD, Wu T-R, Huang G-Y, Zhong Y-Y, Tu B-R, Gao M, Zhou J, Zhao S-Q. The biological evaluation of fusidic acid and its hydrogenation derivative as antimicrobial and anti-inflammatory agents. Infect Drug Resist. 1945;2018:11.","journal-title":"Infect Drug Resist"},{"key":"3181_CR26","doi-asserted-by":"publisher","first-page":"S23","DOI":"10.1016\/S0924-8579(98)00071-5","volume":"12","author":"J Turnidge","year":"1999","unstructured":"Turnidge J. Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents. 1999;12:S23\u201334.","journal-title":"Int J Antimicrob Agents"},{"issue":"4","key":"3181_CR27","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1080\/10408347.2015.1084225","volume":"46","author":"MM Curbete","year":"2016","unstructured":"Curbete MM, Salgado HRN. A critical review of the properties of fusidic acid and analytical methods for its determination. Crit Rev Anal Chem. 2016;46(4):352\u201360.","journal-title":"Crit Rev Anal Chem"},{"key":"3181_CR28","doi-asserted-by":"publisher","first-page":"759220","DOI":"10.3389\/fphar.2021.759220","volume":"12","author":"J Long","year":"2021","unstructured":"Long J, Ji W, Zhang D, Zhu Y, Bi Y. Bioactivities and structure\u2013activity relationships of fusidic acid derivatives: a review. Front Pharmacol. 2021;12:759220.","journal-title":"Front Pharmacol"},{"key":"3181_CR29","volume-title":"Method for antifungal disk diffusion susceptibility testing of yeasts","author":"CLSI","year":"2018","unstructured":"CLSI. Method for antifungal disk diffusion susceptibility testing of yeasts. 3rd ed. Wayne: M44 Clinical and Laboratory Standards Institute; 2018.","edition":"3"},{"issue":"21","key":"3181_CR30","doi-asserted-by":"publisher","first-page":"13088","DOI":"10.3390\/ijms232113088","volume":"23","author":"S Cavalu","year":"2022","unstructured":"Cavalu S, Elbaramawi SS, Eissa AG, Radwan MF, Ibrahim TS, Khafagy E-S, Lopes BS, Ali MAM, Hegazy WAH, Elfaky MA. Characterization of the anti-biofilm and anti-quorum sensing activities of the beta-adrenoreceptor antagonist atenolol against gram-negative bacterial pathogens. Int J Mol Sci. 2022;23(21):13088.","journal-title":"Int J Mol Sci"},{"key":"3181_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40694-018-0046-5","volume":"5","author":"Z Shahina","year":"2018","unstructured":"Shahina Z, El-Ganiny AM, Minion J, Whiteway M, Sultana T, Dahms TE. Cinnamomum zeylanicum bark essential oil induces cell wall remodelling and spindle defects in Candida albicans. Fungal Biol Biotechnol. 2018;5:1\u201316.","journal-title":"Fungal Biol Biotechnol"},{"issue":"10","key":"3181_CR32","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.3390\/microorganisms10101976","volume":"10","author":"AK Thabit","year":"2022","unstructured":"Thabit AK, Eljaaly K, Zawawi A, Ibrahim TS, Eissa AG, Elbaramawi SS, Hegazy WAH, Elfaky MA. Silencing of Salmonella typhimurium pathogenesis: atenolol acquires efficient anti-virulence activities. Microorganisms. 2022;10(10):1976.","journal-title":"Microorganisms"},{"key":"3181_CR33","doi-asserted-by":"publisher","first-page":"2101","DOI":"10.3389\/fmicb.2017.02101","volume":"8","author":"X Liu","year":"2017","unstructured":"Liu X, Li T, Wang D, Yang Y, Sun W, Liu J, Sun S. Synergistic antifungal effect of fluconazole combined with licofelone against resistant Candida albicans. Front Microbiol. 2017;8:2101.","journal-title":"Front Microbiol"},{"issue":"2","key":"3181_CR34","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.bbrc.2005.03.009","volume":"330","author":"S Yamamoto","year":"2005","unstructured":"Yamamoto S, Hiraga K, Abiko A, Hamanaka N, Oda K. A new function of isonitrile as an inhibitor of the Pdr5p multidrug ABC transporter in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 2005;330(2):622\u20138.","journal-title":"Biochem Biophys Res Commun"},{"issue":"53","key":"3181_CR35","doi-asserted-by":"publisher","first-page":"55042","DOI":"10.1074\/jbc.M408881200","volume":"279","author":"N Asthana","year":"2004","unstructured":"Asthana N, Yadav SP, Ghosh JK. Dissection of antibacterial and toxic activity of melittin: a leucine zipper motif plays a crucial role in determining its hemolytic activity but not antibacterial activity. J Biol Chem. 2004;279(53):55042\u201350.","journal-title":"J Biol Chem"},{"issue":"4","key":"3181_CR36","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212 \u0394\u0394CT method. Methods. 2001;25(4):402\u20138.","journal-title":"Methods"},{"issue":"12","key":"3181_CR37","doi-asserted-by":"publisher","first-page":"2564","DOI":"10.3390\/microorganisms9122564","volume":"9","author":"M Askoura","year":"2021","unstructured":"Askoura M, Almalki AJ, Lila ASA, Almansour K, Alshammari F, Khafagy E-S, Ibrahim TS, Hegazy WAH. Alteration of Salmonella enterica virulence and host pathogenesis through targeting sdiA by using the CRISPR-Cas9 system. Microorganisms. 2021;9(12):2564.","journal-title":"Microorganisms"},{"issue":"1","key":"3181_CR38","doi-asserted-by":"publisher","first-page":"57","DOI":"10.3390\/pathogens11010057","volume":"11","author":"M Askoura","year":"2022","unstructured":"Askoura M, Abbas HA, Al Sadoun H, Abdulaal WH, Abu Lila AS, Almansour K, Alshammari F, Khafagy E-S, Ibrahim TS, Hegazy WAH. Elevated levels of IL-33, IL-17 and IL-25 indicate the progression from chronicity to hepatocellular carcinoma in hepatitis C virus patients. Pathogens. 2022;11(1):57.","journal-title":"Pathogens"},{"issue":"10","key":"3181_CR39","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1111\/myc.12204","volume":"57","author":"JY Zhang","year":"2014","unstructured":"Zhang JY, Liu JH, Liu FD, Xia YH, Wang J, Liu X, Zhang ZQ, Zhu N, Ying Y, Huang XT. Vulvovaginal candidiasis: species distribution, fluconazole resistance and drug efflux pump gene overexpression. Mycoses. 2014;57(10):584\u201391.","journal-title":"Mycoses"},{"key":"3181_CR40","volume-title":"Molecular operating environment (MOE) version 2019.0102","author":"Inc CCG","year":"2019","unstructured":"Inc CCG. Molecular operating environment (MOE) version 2019.0102. Montreal: Chemical Computing Group Inc; 2019."},{"issue":"19","key":"3181_CR41","doi-asserted-by":"publisher","first-page":"7329","DOI":"10.1073\/pnas.0401648101","volume":"101","author":"T Jones","year":"2004","unstructured":"Jones T, Federspiel NA, Chibana H, Dungan J, Kalman S, Magee BB, Newport G, Thorstenson YR, Agabian N, Magee PT, Davis RW. The diploid genome sequence of Candida albicans. Proc Natl Acad Sci U S A. 2004;101(19):7329\u201334.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"3181_CR42","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1128\/AAC.39.2.422","volume":"39","author":"M Goldway","year":"1995","unstructured":"Goldway M, Teff D, Schmidt R, Oppenheim AB, Koltin Y. Multidrug resistance in Candida albicans: disruption of the BENr gene. Antimicrob Agents Chemother. 1995;39(2):422\u20136.","journal-title":"Antimicrob Agents Chemother"},{"issue":"4","key":"3181_CR43","first-page":"2007","volume":"8","author":"M van het Hoog","year":"2007","unstructured":"van het Hoog M, Rast TJ, Martchenko M, Grindle S, Dignard D, Hogues H, Cuomo C, Berriman M, Scherer S, Magee BB, Whiteway M. Assembly of the Candida albicans genome into sixteen supercontigs aligned on the eight chromosomes. Genome biologyl. 2007;8(4):2007\u20138.","journal-title":"Genome biologyl"},{"issue":"9","key":"3181_CR44","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1186\/gb-2013-14-9-r97","volume":"14","author":"D Muzzey","year":"2013","unstructured":"Muzzey D, Schwartz K, Weissman JS, Sherlock G. Assembly of a phased diploid Candida albicans genome facilitates allele-specific measurements and provides a simple model for repeat and indel structure. Genome Biol. 2013;14(9):2013\u20134.","journal-title":"Genome Biol"},{"issue":"Pt 2","key":"3181_CR45","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1099\/00221287-143-2-405","volume":"143","author":"D Sanglard","year":"1997","unstructured":"Sanglard D, Ischer F, Monod M, Bille J. Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene. Microbiology. 1997;143(Pt 2):405\u201316.","journal-title":"Microbiology"},{"issue":"12","key":"3181_CR46","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1080\/03639045.2022.2070760","volume":"47","author":"FS Aleanizy","year":"2021","unstructured":"Aleanizy FS, Taha EI, Salem-Bekhit MM, Felimban AM, Al-Suwayeh SA, Al-Joufi FA, Muharram MM, Alqahtani FY, Shakeel F, Youssof AM. Formulation and in vitro and in vivo evaluation of surfactant-stabilized mucoadhesive nanogels for vaginal delivery of fluconazole. Drug Dev Ind Pharm. 2021;47(12):1935\u201342.","journal-title":"Drug Dev Ind Pharm"},{"key":"3181_CR47","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3389\/fmicb.2017.00771","volume":"8","author":"JE Mu\u00f1oz","year":"2017","unstructured":"Mu\u00f1oz JE, Rossi DC, Ishida K, Spadari CC, Melhem MS, Garcia DM, Caires AC, Taborda CP, Rodrigues EG. Antifungal activity of the biphosphinic cyclopalladate C7a against Candida albicans yeast forms in vitro and in vivo. Front Microbiol. 2017;8:771.","journal-title":"Front Microbiol"},{"key":"3181_CR48","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.3389\/fmicb.2019.01466","volume":"10","author":"S Qu","year":"2019","unstructured":"Qu S, Chen L, Tian H, Wang Z, Wang F, Wang L, Li J, Ji H, Xi L, Feng Z. Effect of perillaldehyde on prophylaxis and treatment of vaginal candidiasis in a murine model. Fronti Microbiol. 2019;10:1466.","journal-title":"Fronti Microbiol"},{"issue":"3\u20134","key":"3181_CR49","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1159\/000453134","volume":"40","author":"M Gao","year":"2016","unstructured":"Gao M, Wang H, Zhu L. Quercetin assists fluconazole to inhibit biofilm formations of fluconazole-resistant Candida albicans in in vitro and in vivo antifungal managements of vulvovaginal candidiasis. Cell Physiol Biochem. 2016;40(3\u20134):727\u201342.","journal-title":"Cell Physiol Biochem"},{"issue":"2","key":"3181_CR50","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1128\/MMBR.00045-10","volume":"75","author":"RS Shapiro","year":"2011","unstructured":"Shapiro RS, Robbins N, Cowen LE. Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol Mol Biol Rev. 2011;75(2):213\u201367.","journal-title":"Microbiol Mol Biol Rev"},{"key":"3181_CR51","unstructured":"World Health Organization Antimicrobial resistance: global report on surveillance 2014. Geneva: WHO; 2014."},{"issue":"10","key":"3181_CR52","doi-asserted-by":"publisher","first-page":"3211","DOI":"10.1099\/mic.0.2007\/010405-0","volume":"153","author":"RD Cannon","year":"2007","unstructured":"Cannon RD, Lamping E, Holmes AR, Niimi K, Tanabe K, Niimi M, Monk BC. Candida albicans drug resistance\u2013another way to cope with stress. Microbiology. 2007;153(10):3211\u20137.","journal-title":"Microbiology"},{"issue":"3","key":"3181_CR53","doi-asserted-by":"publisher","first-page":"461","DOI":"10.3390\/antibiotics12030461","volume":"12","author":"AS Abu Lila","year":"2023","unstructured":"Abu Lila AS, Alharby TN, Alanazi J, Alanazi M, Abdallah MH, Rizvi SMD, Moin A, Khafagy E-S, Tabrez S, Al Balushi AA. Clinical resistant strains of Enterococci and their correlation to reduced susceptibility to biocides: phenotypic and genotypic analysis of macrolides, lincosamides, and streptogramins. Antibiotics. 2023;12(3):461.","journal-title":"Antibiotics"},{"issue":"1","key":"3181_CR54","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1093\/jac\/dki171","volume":"56","author":"K Poole","year":"2005","unstructured":"Poole K. Efflux-mediated antimicrobial resistance. J Antimicrob Chemother. 2005;56(1):20\u201351.","journal-title":"J Antimicrob Chemother"},{"issue":"3","key":"3181_CR55","doi-asserted-by":"publisher","first-page":"178","DOI":"10.2174\/1871526517666170531114335","volume":"17","author":"B Pourakbari","year":"2017","unstructured":"Pourakbari B, Teymuri M, Mahmoudi S. K Valian S, Movahedi Z, Eshaghi H, Mamishi S: Expression of major efflux pumps in fluconazole-resistant Candida albicans. Infect Disord Drug Targets. 2017;17(3):178\u201384.","journal-title":"Infect Disord Drug Targets"},{"issue":"2","key":"3181_CR56","doi-asserted-by":"publisher","first-page":"285","DOI":"10.33594\/000000139","volume":"53","author":"YS Bae","year":"2019","unstructured":"Bae YS, Rhee MS. Short-term antifungal treatments of caprylic acid with carvacrol or thymol induce synergistic 6-log reduction of pathogenic Candida albicans by cell membrane disruption and efflux pump inhibition. Cell Physiol Biochem. 2019;53(2):285\u2013300.","journal-title":"Cell Physiol Biochem"},{"issue":"2","key":"3181_CR57","first-page":"60","volume":"12","author":"N Akhtar","year":"2022","unstructured":"Akhtar N, Ayoubi R, Kour V, Gautam U, Mannan AU. Natural products for fungal diseases management and prevention. Nat Prod J. 2022;12(2):60\u20139.","journal-title":"Nat Prod J"},{"issue":"3","key":"3181_CR58","doi-asserted-by":"publisher","first-page":"484","DOI":"10.3390\/scipharm84030484","volume":"84","author":"KA Agha","year":"2016","unstructured":"Agha KA, Abo-Dya NE, Ibrahim TS, Abdel-Aal EH, Hegazy WA. Benzotriazole-mediated synthesis and antibacterial activity of novel n-acylcephalexins. Sci Pharm. 2016;84(3):484\u201396.","journal-title":"Sci Pharm"},{"issue":"3","key":"3181_CR59","doi-asserted-by":"publisher","first-page":"671","DOI":"10.3390\/molecules27030671","volume":"27","author":"AJ Almalki","year":"2022","unstructured":"Almalki AJ, Ibrahim TS, Taher ES, Mohamed MFA, Youns M, Hegazy WAH, Al-Mahmoudy AMM. Synthesis, antimicrobial, anti-virulence and anticancer evaluation of new 5(4h)-oxazolone-based sulfonamides. Molecules. 2022;27(3):671.","journal-title":"Molecules"},{"issue":"14","key":"3181_CR60","doi-asserted-by":"publisher","first-page":"718","DOI":"10.5897\/AJB2016.15852","volume":"16","author":"WAH Hegazy","year":"2017","unstructured":"Hegazy WAH, Abbas HA. Evaluation of the role of SsaV \u2018Salmonella pathogenicity island-2 dependent type III secretion system components on the virulence behavior of Salmonella enterica serovar Typhimurium. Afr J Biotech. 2017;16(14):718\u201326.","journal-title":"Afr J Biotech"},{"issue":"3","key":"3181_CR61","doi-asserted-by":"publisher","first-page":"357","DOI":"10.3390\/ph15030357","volume":"15","author":"MN Alandiyjany","year":"2022","unstructured":"Alandiyjany MN, Abdelaziz AS, Abdelfattah-Hassan A, Hegazy WAH, Hassan AA, Elazab ST, Mohamed EAA, El-Shetry ES, Saleh AA, ElSawy NA, Ibrahim D. Novel in vivo assessment of antimicrobial efficacy of ciprofloxacin loaded mesoporous silica nanoparticles against Salmonella typhimurium infection. Pharmaceuticals. 2022;15(3):357.","journal-title":"Pharmaceuticals"},{"key":"3181_CR62","volume-title":"Hepatotoxicity and hyperbilirubinemia of fusidic acid and rifampin: review of literature","author":"M Pickl","year":"1987","unstructured":"Pickl M. Hepatotoxicity and hyperbilirubinemia of fusidic acid and rifampin: review of literature. 1987."},{"key":"3181_CR63","unstructured":"Pedersen JM. ATP-Binding-Cassette transporters in biliary efflux and drug-induced liver injury. Acta Universitatis Upsaliensis. Sweden: PhD thesis, Uppsala University; 2013."},{"issue":"10","key":"3181_CR64","doi-asserted-by":"publisher","first-page":"5858","DOI":"10.1128\/AAC.01252-16","volume":"60","author":"S Bhattacharya","year":"2016","unstructured":"Bhattacharya S, Sobel JD, White TC. A combination fluorescence assay demonstrates increased efflux pump activity as a resistance mechanism in azole-resistant vaginal Candida albicans isolates. Antimicrob Agents Chemother. 2016;60(10):5858\u201366.","journal-title":"Antimicrob Agents Chemother"},{"key":"3181_CR65","doi-asserted-by":"publisher","first-page":"211","DOI":"10.3389\/fcimb.2019.00211","volume":"9","author":"J Xu","year":"2019","unstructured":"Xu J, Liu R, Sun F, An L, Shang Z, Kong L, Yang M. Eucalyptal D enhances the antifungal effect of fluconazole on fluconazole-resistant Candida albicans by competitively inhibiting efflux pump. Front Cell Infect Microbiol. 2019;9:211.","journal-title":"Front Cell Infect Microbiol"},{"issue":"4","key":"3181_CR66","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1128\/AAC.00940-08","volume":"53","author":"L Sun","year":"2009","unstructured":"Sun L, Sun S, Cheng A, Wu X, Zhang Y, Lou H. In vitro activities of retigeric acid B alone and in combination with azole antifungal agents against Candida albicans. Antimicrob Agents Chemother. 2009;53(4):1586\u201391.","journal-title":"Antimicrob Agents Chemother"},{"key":"3181_CR67","doi-asserted-by":"publisher","first-page":"111568","DOI":"10.1016\/j.biopha.2021.111568","volume":"139","author":"Y Wang","year":"2021","unstructured":"Wang Y, Lu C, Zhao X, Wang D, Liu Y, Sun S. Antifungal activity and potential mechanism of Asiatic acid alone and in combination with fluconazole against Candida albicans. Biomed Pharmacother. 2021;139:111568.","journal-title":"Biomed Pharmacother"},{"key":"3181_CR68","doi-asserted-by":"publisher","first-page":"110580","DOI":"10.1016\/j.biopha.2020.110580","volume":"130","author":"Y Liu","year":"2020","unstructured":"Liu Y, Ren H, Wang D, Zhang M, Sun S, Zhao Y. The synergistic antifungal effects of gypenosides combined with fluconazole against resistant Candida albicans via inhibiting the drug efflux and biofilm formation. Biomed Pharmacother. 2020;130:110580.","journal-title":"Biomed Pharmacother"},{"issue":"4","key":"3181_CR69","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1021\/np050396y","volume":"69","author":"X-C Li","year":"2006","unstructured":"Li X-C, Jacob MR, Ding Y, Agarwal AK, Smillie TJ, Khan SI, Nagle DG, Ferreira D, Clark AM. Capisterones A and B, which enhance fluconazole activity in Saccharomyces cerevisiae, from the marine green alga Penicillus capitatus. J Nat Prod. 2006;69(4):542\u20136.","journal-title":"J Nat Prod"},{"issue":"1\u20132","key":"3181_CR70","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.ejps.2012.09.016","volume":"48","author":"A Ahmad","year":"2013","unstructured":"Ahmad A, Khan A, Manzoor N. Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole. Eur J Pharm Sci. 2013;48(1\u20132):80\u20136.","journal-title":"Eur J Pharm Sci"},{"key":"3181_CR71","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.jgar.2020.10.025","volume":"24","author":"H Chen","year":"2021","unstructured":"Chen H, Li H, Duan C, Song C, Peng Z, Shi W. Reversal of azole resistance in Candida albicans by oridonin. J Glob Antimicrob Resist. 2021;24:296\u2013302.","journal-title":"J Glob Antimicrob Resist"},{"issue":"3","key":"3181_CR72","doi-asserted-by":"publisher","first-page":"2914","DOI":"10.3390\/ijms24032914","volume":"24","author":"IP S\u00e6b\u00f8","year":"2023","unstructured":"S\u00e6b\u00f8 IP, Bj\u00f8r\u00e5s M, Franzyk H, Helgesen E, Booth JA. Optimization of the hemolysis assay for the assessment of cytotoxicity. Int J Mol Sci. 2023;24(3):2914.","journal-title":"Int J Mol Sci"},{"issue":"2","key":"3181_CR73","doi-asserted-by":"publisher","first-page":"483","DOI":"10.3390\/ijms22020483","volume":"22","author":"M Ivanov","year":"2021","unstructured":"Ivanov M, Kannan A, Stojkovi\u0107 DS, Glamo\u010dlija J, Calhelha RC, Ferreira IC, Sanglard D, Sokovi\u0107 M. Camphor and eucalyptol\u2014Anticandidal spectrum, antivirulence effect, efflux pumps interference and cytotoxicity. Int J Mol Sci. 2021;22(2):483.","journal-title":"Int J Mol Sci"},{"issue":"5","key":"3181_CR74","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1093\/jac\/dkh434","volume":"54","author":"M Cuenca-Estrella","year":"2004","unstructured":"Cuenca-Estrella M. Combinations of antifungal agents in therapy\u2013what value are they? J Antimicrob Chemother. 2004;54(5):854\u201369.","journal-title":"J Antimicrob Chemother"},{"key":"3181_CR75","doi-asserted-by":"publisher","first-page":"9411","DOI":"10.2147\/IJN.S229557","volume":"14","author":"AM Eid","year":"2019","unstructured":"Eid AM, Istateyeh I, Salhi N, Istateyeh T. Antibacterial activity of Fusidic acid and sodium Fusidate nanoparticles incorporated in pine oil Nanoemulgel. Int J Nanomed. 2019;14:9411\u201321.","journal-title":"Int J Nanomed"}],"container-title":["BMC Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12866-024-03181-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12866-024-03181-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12866-024-03181-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T08:03:26Z","timestamp":1707552206000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmicrobiol.biomedcentral.com\/articles\/10.1186\/s12866-024-03181-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,10]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["3181"],"URL":"https:\/\/doi.org\/10.1186\/s12866-024-03181-z","relation":{},"ISSN":["1471-2180"],"issn-type":[{"value":"1471-2180","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,10]]},"assertion":[{"value":"30 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The current study was performed in accordance with the Helsinki Declaration, and informed consent has been obtained from the subjects. The Institutional Review Board (IRB) approved this study under the number ZU-IRB #10395. All animal procedures used were approved by Zagazig University\u2019s Institutional Animal Care and Use Committee (ZU-IACUC), Egypt, with approval number (ZU-IACUC\/3\/F\/399\/2022).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors are consent for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"54"}}