{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:19:41Z","timestamp":1790104781727,"version":"4.0.1"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research at Jouf University","award":["DSR2020-04-2540"],"award-info":[{"award-number":["DSR2020-04-2540"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Reboxetine (REB) and sertraline (SER) are antidepressants. The antifungal potential of these drugs against planktonic Candida has been recently reported with limited data about their effects on Candidal biofilms. Biofilms are self-derived extracellular matrixes produced by the microbial population that is attached to biotic surfaces, such as vaginal and oral mucosa, or abiotic surfaces, such as biomedical devices, resulting in persistent fungal infections. The commonly prescribed antifungals, azoles, are usually less effective when biofilms are formed, and most of the prescribed antifungals are only fungistatic. Therefore, the current study investigates the antifungal potentials of REB and SER, alone and in combination with fluconazole (FLC) and itraconazole (ITR) against Candidal biofilms. Using proper controls, Candida species (Candida albicans, C. albicans; Candida krusei, C. krusei; and Candida glabrata, C. glabrata) were used to form biofilms in 96-well microplates. Serial dilutions corresponding to concentrations ranging from 2 to 4096 \u00b5g\/mL of the target drugs (REB, SER, FLC, ITR) were prepared and added to the plates. Impairment of the biofilm biomass and biofilm metabolic viability was detected using the crystal violet (CV) assay and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, respectively. In the checkerboard assay, the sessile fractional inhibitory concentration index (SFICI) was calculated to evaluate the effects of drug combinations. SER was more effective in reducing the biomass than REB for C. albicans and C. glabrata, but both were equal for C. krusei. For the reduction in metabolic activity in C. albicans and C. glabrata, SER had a slight advantage over REB. In C. krusei, REB was slightly more potent. Overall, FLC and ITR were almost equal and produced more significant reductions in metabolic activity when compared to SER and REB, except for C. glabrata, where SER was almost equal to FLC. Synergism was detected between REB + FLC and REB + ITR against biofilm cells of C. albicans. Synergism was detected between REB + ITR against biofilm cells of C. krusei. Synergism was detected between REB + FLC and REB + ITR against biofilm cells of C. albicans, C. krusei, and C. glabrata. The results of the present study support the potential of SER and REB as anti-Candidal biofilm agents that are beneficial as a new antifungal to combat Candidal resistance.<\/jats:p>","DOI":"10.3390\/antibiotics12050881","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T03:32:27Z","timestamp":1683689547000},"page":"881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anti-Candidal Activity of Reboxetine and Sertraline Antidepressants: Effects on Pre-Formed Biofilms"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5220-4521","authenticated-orcid":false,"given":"Eman Ibrahim","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Alhuwaydi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5766-4495","authenticated-orcid":false,"given":"Ahmed E.","family":"Taha","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology Unit, Department of Pathology, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"},{"name":"Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Abouelkheir","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"},{"name":"Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"ref_1","first-page":"490.e1","article-title":"Invasive infections due to filamentous fungi other than Aspergillus: Epidemiology and determinants of mortality","volume":"21","author":"Slavin","year":"2015","journal-title":"Mycology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"607","DOI":"10.2147\/IDR.S237815","article-title":"Emerging Invasive Fungal Infections: Clinical Features and Controversies in Diagnosis and Treatment Processes","volume":"13","author":"Zhang","year":"2020","journal-title":"Infect. Drug Resist."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.2147\/IDR.S124918","article-title":"Antifungal resistance: Current trends and future strategies to combat","volume":"10","author":"Wiederhold","year":"2017","journal-title":"Infect. Drug Resist."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6179","DOI":"10.1128\/AAC.03046-15","article-title":"The synergistic effect of azoles and fluoxetine against resistant Candida albicans strains is attributed to attenuating fungal virulence","volume":"60","author":"Gu","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1099\/jmm.0.045054-0","article-title":"Candida species: Current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options","volume":"62","author":"Sardi","year":"2013","journal-title":"J. Med. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.4314\/ahs.v18i4.37","article-title":"Relationship between Sap prevalence and biofilm formation among resistant clinical isolates of Candida albicans","volume":"18","author":"Kadry","year":"2018","journal-title":"Afr. Health Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"El-Telbany, M., Mohamed, A.A., Yahya, G., Abdelghafar, A., Abdel-Halim, M.S., Saber, S., Alfaleh, M.A., Mohamed, A.H., Abdelrahman, F., and Fathey, H.A. (2022). Combination of Meropenem and Zinc Oxide Nanoparticles; Antimicrobial Synergism, Exaggerated Antibiofilm Activity, and Efficient Therapeutic Strategy against Bacterial Keratitis. Antibiotics, 11.","DOI":"10.3390\/antibiotics11101374"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41429-022-00566-y","article-title":"In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates","volume":"75","author":"Askoura","year":"2022","journal-title":"J. Antibiot."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"El-Baz, A.M., Mosbah, R.A., Goda, R.M., Mansour, B., Sultana, T., Dahms, T.E.S., and El-Ganiny, A.M. (2021). Back to Nature: Combating Candida albicans Biofilm, Phospholipase and Hemolysin Using Plant Essential Oils. Antibiotics, 10.","DOI":"10.3390\/antibiotics10010081"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/j.1439-0507.2008.01550.x","article-title":"The expression of genes involved in the ergosterol biosynthesis pathway in Candida albicans and Candida dubliniensis biofilms exposed to fluconazole","volume":"52","author":"Moran","year":"2009","journal-title":"Mycoses"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2174\/2211362611208020095","article-title":"Evaluation of in vivo and in vitro antimicrobial activities of a selective serotonin reuptake inhibitor sertraline hydrochloride","volume":"10","author":"Samanta","year":"2012","journal-title":"Anti-Infect. Agents"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1128\/AAC.02623-13","article-title":"Anti-Candida activity of fluoxetine alone and combined with fluconazole: A synergistic action against fluconazole-resistant strains","volume":"58","author":"Oliveira","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s12223-016-0449-8","article-title":"In vitro synergistic effects of chlorpromazine and sertraline in combination with amphotericin B against Cryptococcus neoformans var","volume":"61","author":"Rossato","year":"2016","journal-title":"grubii. Folia Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.micpath.2017.04.008","article-title":"In vitro anti-Candida activity of selective serotonin reuptake inhibitors against fluconazole-resistant strains and their activity against biofilm-forming isolates","volume":"107","author":"Campos","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1534\/genetics.110.117846","article-title":"The antidepressant sertraline targets intracellular vesiculogenic membranes in yeast","volume":"185","author":"Rainey","year":"2010","journal-title":"Genetics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/msb.2011.31","article-title":"Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole","volume":"7","author":"Spitzer","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1128\/AAC.00212-12","article-title":"The antidepressant sertraline provides a promising therapeutic option for neurotropic Cryptococcal infections","volume":"56","author":"Zhai","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"26883","DOI":"10.1038\/srep26883","article-title":"Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study","volume":"6","author":"Zheng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1124\/jpet.102.046532","article-title":"Inhibition of P-glycoprotein by newer antidepressants","volume":"305","author":"Weiss","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2174\/2211556004666150520230121","article-title":"Antimicrobial properties of various psychotropic drugs against broad range microorganisms","volume":"3","author":"Kalayci","year":"2014","journal-title":"Curr. Psychopharmacol."},{"key":"ref_21","first-page":"165rv13","article-title":"Hidden killers: Human fungal infections","volume":"2","author":"Brown","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s00430-018-0539-0","article-title":"Anti-Candida activity of antidepressants sertraline and fluoxetine: Effect upon pre-formed biofilms","volume":"207","author":"Oliveira","year":"2018","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1128\/AAC.45.9.2475-2479.2001","article-title":"Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms","volume":"45","author":"Ramage","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.mimet.2007.11.010","article-title":"Comparison of multiple methods for quantification of microbial biofilms grown in microtiter plates","volume":"72","author":"Peeters","year":"2008","journal-title":"J. Microbiol. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s11046-011-9448-0","article-title":"AntiCandidal efficacy of cinnamon oil against planktonic and biofilm cultures of Candida parapsilosis and Candida orthopsilosis","volume":"172","author":"Pires","year":"2011","journal-title":"Mycopathologia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1038\/nprot.2008.141","article-title":"A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing","volume":"3","author":"Pierce","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.3389\/fmicb.2018.02892","article-title":"Strong Synergism of Palmatine and Fluconazole\/Itraconazole Against Planktonic and Biofilm Cells of Candida Species and Efflux-Associated Antifungal Mechanism","volume":"9","author":"Wan","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/jam.12555","article-title":"Matrine reduces yeast-to-hypha transition and resistance of a fluconazole resistant strain of Candida albicans","volume":"117","author":"Shao","year":"2014","journal-title":"J. Appl. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jgar.2022.01.030","article-title":"Serotonin reuptake inhibitors effect on fluconazole activity against resistant Candida glabrata strains","volume":"29","author":"Alkhalifa","year":"2022","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_30","first-page":"17","article-title":"Antifungal and Antibiofilm Activities of Selective Serotonin Reuptake Inhibitors Alone and in Combination with Fluconazole","volume":"23","author":"Temel","year":"2020","journal-title":"Turk. J. Pharm. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1086\/324589","article-title":"Antifungal activity against Candida species of the selective serotonin reuptake inhibitor, sertraline","volume":"33","author":"Dierich","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_32","unstructured":"(2023, January 21). Sertraline Hydrochloride. Available online: https:\/\/go.drugbank.com\/salts\/DBSALT000808."},{"key":"ref_33","unstructured":"(2023, January 21). Reboxetine. Available online: https:\/\/go.drugbank.com\/drugs\/DB00234."},{"key":"ref_34","first-page":"177","article-title":"Correlation between the lipophilicity and antifungal activity of some benzoxazole derivatives","volume":"41","year":"2010","journal-title":"Acta Period. Technol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"391","DOI":"10.2165\/00023210-200014050-00006","article-title":"Sertraline","volume":"14","author":"Comer","year":"2000","journal-title":"CNS Drugs"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"413","DOI":"10.2165\/00003088-200039060-00003","article-title":"Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression","volume":"39","author":"Fleishaker","year":"2000","journal-title":"Clin. Pharmacokinet."},{"key":"ref_37","unstructured":"Foye, W., Lemke, T., and Williams, D. (2008). FOYE\u2019S Principles of Medicinal Chemistry, Lippincott Williams & Wilkins. [6th ed.]."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"254","DOI":"10.5414\/CPP38254","article-title":"Pharmacokinetics of reboxetine in elderly patients with depressive disorders","volume":"38","author":"Poggesi","year":"2000","journal-title":"Int. J. Clin. Pharmacol. Ther."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/5\/881\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:32:05Z","timestamp":1760124725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/5\/881"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,9]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["antibiotics12050881"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12050881","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,9]]}}}