{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:16:58Z","timestamp":1791245818954,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T00:00:00Z","timestamp":1730764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"S\u00e3o Paulo State Research Foundation","award":["2015\/01017-0"],"award-info":[{"award-number":["2015\/01017-0"]}]},{"name":"S\u00e3o Paulo State Research Foundation","award":["2019\/17721-9"],"award-info":[{"award-number":["2019\/17721-9"]}]},{"name":"S\u00e3o Paulo State Research Foundation","award":["304247\/2021-9"],"award-info":[{"award-number":["304247\/2021-9"]}]},{"name":"S\u00e3o Paulo State Research Foundation","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Brazilian National Council for Scientific and Technological Development","award":["2015\/01017-0"],"award-info":[{"award-number":["2015\/01017-0"]}]},{"name":"Brazilian National Council for Scientific and Technological Development","award":["2019\/17721-9"],"award-info":[{"award-number":["2019\/17721-9"]}]},{"name":"Brazilian National Council for Scientific and Technological Development","award":["304247\/2021-9"],"award-info":[{"award-number":["304247\/2021-9"]}]},{"name":"Brazilian National Council for Scientific and Technological Development","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brazil","award":["2015\/01017-0"],"award-info":[{"award-number":["2015\/01017-0"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brazil","award":["2019\/17721-9"],"award-info":[{"award-number":["2019\/17721-9"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brazil","award":["304247\/2021-9"],"award-info":[{"award-number":["304247\/2021-9"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior-Brazil","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","award":["2015\/01017-0"],"award-info":[{"award-number":["2015\/01017-0"]}]},{"name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","award":["2019\/17721-9"],"award-info":[{"award-number":["2019\/17721-9"]}]},{"name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","award":["304247\/2021-9"],"award-info":[{"award-number":["304247\/2021-9"]}]},{"name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Numerous Candida species are responsible for fungal infections; however, Candida albicans stands out among the others. Treatment with fluconazole is often ineffective due to the resistance phenotype mediated by transmembrane transporters and\/or biofilm formation, mechanisms of resistance commonly found in C. albicans strains. A previous study by our group demonstrated that batzelladine D can inhibit the Pdr5p transporter in Saccharomyces cerevisiae. In the present study, our aim was to investigate the efficacy of batzelladine D in inhibiting the main efflux pumps of Candida albicans, CaCdr1p and CaCdr2p, as well as to evaluate the effect of the compound on C. albicans biofilm. Assays were conducted using a clinical isolate of Candida albicans expressing both transporters. Additionally, to allow the study of each transporter, S. cerevisiae mutant strains overexpressing CaCdr1p or CaCdr2p were used. Batzelladine D was able to reverse the fluconazole resistance phenotype by acting on both transporters. The compound synergistically improved the effect of fluconazole against the clinical isolate when tested in the Caenorhabditis elegans animal model. Moreover, the compound disrupted the preformed biofilm. Based on the obtained data, the continuation of batzelladine D studies as a potential new antifungal agent and\/or chemosensitizer in Candida albicans infections can be suggested.<\/jats:p>","DOI":"10.3390\/md22110502","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T06:30:48Z","timestamp":1730788248000},"page":"502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Batzelladine D, a Marine Natural Product, Reverses the Fluconazole Resistance Phenotype Mediated by Transmembrane Transporters in Candida albicans and Interferes with Its Biofilm: An In Vitro and In Silico Study"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9970-3683","authenticated-orcid":false,"given":"Levy T. S.","family":"Domingos","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"de Moraes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rio F. C.","family":"Santos","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica de S\u00e3o Carlos, Universidade de S\u00e3o Paulo, CP 780, S\u00e3o Carlos 13560-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A. R.","family":"Curvelo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-1761","authenticated-orcid":false,"given":"Brayan","family":"Bayona-Pacheco","sequence":"additional","affiliation":[{"name":"Departamento de Medicina, Divisi\u00f3n Ciencias de la Salud, Universidad del Norte, km 5, V\u00eda Puerto Colombia, \u00c1rea Metropolitana de Barranquilla, Barranquilla 081007, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-1528","authenticated-orcid":false,"given":"Edgar A.","family":"Marquez","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Biologia, Facultad de Ciencias B\u00e1sicas, Universidad del Norte, km 5, V\u00eda Puerto Colombia, \u00c1rea Metropolitana de Barranquilla, Barranquilla 081007, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony W. B.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica y Biologia, Facultad de Ciencias B\u00e1sicas, Universidad del Norte, km 5, V\u00eda Puerto Colombia, \u00c1rea Metropolitana de Barranquilla, Barranquilla 081007, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto G. S.","family":"Berlinck","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica de S\u00e3o Carlos, Universidade de S\u00e3o Paulo, CP 780, S\u00e3o Carlos 13560-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0474-8388","authenticated-orcid":false,"given":"Antonio","family":"Ferreira-Pereira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es (IMPG), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s12281-023-00455-3","article-title":"Candidiasis and other emerging yeasts","volume":"17","author":"Sharma","year":"2023","journal-title":"Curr. Fungal Infect. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"ofac097","DOI":"10.1093\/ofid\/ofac097","article-title":"Economic burden of fungal diseases in the United States","volume":"9","author":"Benedict","year":"2022","journal-title":"Open Forum Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ciurea, C.N., Kosovski, I.B., Mare, A.D., Toma, F., Pintea-Simon, I.A., and Man, A. (2020). Candida and candidiasis-opportunism versus pathogenicity: A review of the virulence traits. Microorganisms, 8.","DOI":"10.3390\/microorganisms8060857"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Parslow, B.Y., and Thornton, C.R. (2022). Continuing shifts in epidemiology and antifungal susceptibility highlight the need for improved disease management of invasive candidiasis. Microorganisms, 10.","DOI":"10.3390\/microorganisms10061208"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3851","DOI":"10.1128\/AAC.00463-08","article-title":"ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates","volume":"52","author":"Holmes","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/jam.14949","article-title":"Biofilm of Candida albicans: Formation, regulation and resistance","volume":"131","author":"Pereira","year":"2021","journal-title":"J. Appl. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.2217\/fmb.13.101","article-title":"Mechanisms of candida biofilm drug resistance","volume":"8","author":"Taff","year":"2013","journal-title":"Future Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Domingos, L.T.S., Santos, M.F.C., de Moraes, D.C., de Sa, L.F.R., da Silva, V.A.D., Meuren, L.M., Berlinck, R.G.S., and Ferreira-Pereira, A. (2020). Batzelladine D and norbatzelladine L purified from marine sponge Monanchora arbuscula induce the reversal of fluconazole. Bioorg. Chem., 105.","DOI":"10.1016\/j.bioorg.2020.104402"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/BF00352101","article-title":"Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals","volume":"27","author":"Prasad","year":"1995","journal-title":"Curr. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1128\/EC.00091-07","article-title":"Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae","volume":"6","author":"Lamping","year":"2007","journal-title":"Eukaryot. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1128\/AAC.46.6.1704-1713.2002","article-title":"Resistance mechanisms in clinical isolates of Candida albicans","volume":"46","author":"White","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1128\/AAC.48.4.1256-1271.2004","article-title":"Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative","volume":"48","author":"Niimi","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1007\/s42770-020-00254-9","article-title":"\u03b2-Lapachone enhances the antifungal activity of fluconazole against a Pdr5p-mediated resistant Saccharomyces cerevisiae strain","volume":"51","author":"Cardoso","year":"2020","journal-title":"Braz. J. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1128\/CMR.00051-08","article-title":"Efflux-mediated antifungal drug resistance","volume":"22","author":"Cannon","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Torres, P.H.M., Sodero, A.C.R., Jofily, P., and Silva, F.P. (2019). Key topics in molecular docking for drug design. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184574"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Singh, S., Fatima, Z., Ahmad, K., and Hameed, S. (2018). Fungicidal action of geraniol against Candida albicans is potentiated by abrogated CaCdr1p drug efflux and fluconazole synergism. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203079"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.7164\/antibiotics.40.1249","article-title":"FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics","volume":"40","author":"Kino","year":"1987","journal-title":"J. Antibiot."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00492-16","DOI":"10.1128\/mBio.00492-16","article-title":"Structures of pathogenic fungal FKBP12s reveal possible self-catalysis function","volume":"7","author":"Tonthat","year":"2016","journal-title":"mBio"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"784","DOI":"10.17344\/acsi.2018.4723","article-title":"Tacrolimus as antifungal agent","volume":"66","author":"Antypenko","year":"2019","journal-title":"Acta Chim. Slov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1590\/S1517-838246120120442","article-title":"Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates","volume":"46","author":"Denardi","year":"2015","journal-title":"Braz. J. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1128\/AAC.02040-12","article-title":"Milbemycins: More than efflux inhibitors for fungal pathogens","volume":"57","author":"Silva","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1021\/acs.jcim.1c01406","article-title":"Observing noncovalent interactions in experimental electron density for macromolecular systems: A novel perspective for protein-ligand interaction research","volume":"62","author":"Ding","year":"2022","journal-title":"J. Chem. Inf. Model."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2174\/092986712803414150","article-title":"Specific noncovalent interactions at protein-ligand interface: Implications for rational drug design","volume":"19","author":"Zhou","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00894-017-3537-z","article-title":"How accurate is the description of ligand-protein interactions by a hybrid QM\/MM approach?","volume":"24","author":"Kollar","year":"2017","journal-title":"J. Mol. Model."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"259","DOI":"10.15557\/JoU.2015.0022","article-title":"Value of ultrasonography in assessment of recent injury of anterior talofibular ligament in children","volume":"15","author":"Szczepaniak","year":"2015","journal-title":"J. Ultrason."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Spassov, D.S., Atanasova, M., and Doytchinova, I. (2022). A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.1066029"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113323","DOI":"10.1016\/j.ecoenv.2022.113323","article-title":"Evaluation of the binding performance of flavonoids to estrogen receptor alpha by Autodock, Autodock Vina and Surflex-Dock","volume":"233","author":"Xue","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Quiroga, R., and Villarreal, M.A. (2016). Vinardo: A scoring function based on autodock vina improves scoring, docking and virtual screening. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155183"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13321-021-00522-2","article-title":"GNINA 1.0: Molecular docking with deep learning","volume":"13","author":"McNutt","year":"2021","journal-title":"J. Cheminform."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Abd Rani, N.Z., Lee, Y.K., Ahmad, S., Meesala, R., and Abdullah, I. (2022). Fused tricyclic guanidine alkaloids: Insights into their structure, synthesis and bioactivity. Mar. Drugs, 20.","DOI":"10.3390\/md20090579"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rollin-Pinheiro, R., Bayona-Pacheco, B., Domingos, L.T.S., da Rocha Curvelo, J.A., de Castro, G.M.M., Barreto-Bergter, E., and Ferreira-Pereira, A. (2021). Sphingolipid inhibitors as an alternative to treat candidiasis caused by fluconazole-resistant strains. Pathogens, 10.","DOI":"10.3390\/pathogens10070856"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1021\/acs.jnatprod.5b00070","article-title":"Anti-parasitic guanidine and pyrimidine alkaloids from the marine sponge Monanchora arbuscula","volume":"78","author":"Santos","year":"2015","journal-title":"J. Nat. Prod."},{"key":"ref_33","first-page":"10","article-title":"Synthetic organotellurium compounds sensitize drug-resistant Candida albicans clinical isolates to fluconazole","volume":"61","author":"Toledo","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1128\/CMR.18.1.163-194.2005","article-title":"Combination treatment of invasive fungal infections","volume":"18","author":"Mukherjee","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Clemente de Moraes, D., do Carmo Freire Ribeiro Pinto, M., Tenorio Sousa Domingos, L., do Valle Pereira Midlej, V., and Ferreira-Pereira, A. (2022). Effects of beta-lapachone and beta-nor-lapachone on multidrug efflux transporters and biofilms of Candida glabrata. Bioorg. Med. Chem., 63.","DOI":"10.1016\/j.bmc.2022.116749"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New docking methods, expanded force field, and python bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Priya, A., and Pandian, S.K. (2020). Piperine impedes biofilm formation and hyphal morphogenesis of Candida albicans. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.00756"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Swetha, T.K., Pooranachithra, M., Subramenium, G.A., Divya, V., Balamurugan, K., and Pandian, S.K. (2019). Umbelliferone impedes biofilm formation and virulence of methicillin-resistant Staphylococcus epidermidis via impairment of initial attachment and intercellular adhesion. Front. Cell. Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00357"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1038\/nprot.2008.193","article-title":"A C. elegans-based, whole animal, in vivo screen for the identification of antifungal compounds","volume":"3","author":"Tampakakis","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Breger, J., Fuchs, B.B., Aperis, G., Moy, T.I., Ausubel, F.M., and Mylonakis, E. (2007). Antifungal chemical compounds identified using a C. elegans pathogenicity assay. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030018"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1021\/ci800305f","article-title":"OSIRIS, an entirely in-house developed drug discovery informatics system","volume":"49","author":"Sander","year":"2009","journal-title":"J. Chem. Inf. Model."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/22\/11\/502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:26:36Z","timestamp":1760113596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/22\/11\/502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,5]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["md22110502"],"URL":"https:\/\/doi.org\/10.3390\/md22110502","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,5]]}}}