{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T17:37:33Z","timestamp":1763141853058,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Brazil (CAPES)","award":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"],"award-info":[{"award-number":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"]}]},{"name":"Rodrigo Rollin-Pinheiro","award":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"],"award-info":[{"award-number":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"]}]},{"name":"Leandro Augusto Barbosa","award":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"],"award-info":[{"award-number":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"]}]},{"name":"Eliana Barreto-Bergter","award":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"],"award-info":[{"award-number":["001","FAPERJ E-26\/200.591\/2022","FAPEMIG: PPM-00307-18","FAPEMIG: APQ-00855-19","CNPq: 305441\/2021-3 e 403646\/2021-9","FAPERJ E-26\/201.208\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>The poor outcome of treatments for fungal infections is a consequence of the increasing incidence of resistance to antifungal agents, mainly due to the overexpression of efflux pumps. To surpass this mechanism of resistance, a substance able to inhibit these pumps could be administered in association with antifungals. Saccharomyces cerevisiae possesses an efflux pump (Pdr5p) homologue to those found in pathogenic yeast. Digoxin is a natural product that inhibits Na+, K+-ATPase. The aim of this study was to evaluate whether digoxin and its derivatives (i.e., DGB, digoxin benzylidene) can inhibit Pdr5p, reversing the resistance to fluconazole in yeasts. An S. cerevisiae mutant strain that overexpresses Pdr5p was used in the assays. The effects of the compounds on yeast growth, efflux activity, and Pdr5p ATPase activity were measured. All derivatives enhanced the antifungal activity of fluconazole against S. cerevisiae, in comparison to fluconazole alone, with FICI values ranging from 0.031 to 0.500. DGB 1 and DGB 3 presented combined effects with fluconazole against a Candida albicans strain, with fractional inhibitory concentration index (FICI) values of 0.625 and 0.281, respectively The compounds also inhibited the efflux of rhodamine 6G and Pdr5p ATPase activity, with IC50 values ranging from 0.41 \u03bcM to 3.72 \u03bcM. The results suggest that digoxin derivatives impair Pdr5p activity. Considering the homology between Pdr5p and efflux pumps from pathogenic fungi, these compounds are potential candidates to be used in association with fluconazole to treat resistant fungal infections.<\/jats:p>","DOI":"10.3390\/jof8080769","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T01:42:13Z","timestamp":1658713333000},"page":"769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Digoxin Derivatives Sensitize a Saccharomyces cerevisiae Mutant Strain to Fluconazole by Inhibiting Pdr5p"],"prefix":"10.3390","volume":"8","author":[{"given":"Daniel Clemente","family":"de Moraes","sequence":"first","affiliation":[{"name":"Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria, Avenida Carlos Chagas Filho 373, Rio de Janeiro 21941-590, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Claudia","family":"Tessis","sequence":"additional","affiliation":[{"name":"Instituto Federal do Rio de Janeiro, Rua Senador Furtado 121, Rio de Janeiro 20270-021, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8316-4670","authenticated-orcid":false,"given":"Rodrigo","family":"Rollin-Pinheiro","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria, Avenida Carlos Chagas Filho 373, Rio de Janeiro 21941-590, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jefferson Luiz","family":"Princival","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biochemistry, Universidade Federal de S\u00e3o Jo\u00e3o del Rei, Campus Centro-Oeste Dona Lindu, Avenida Sebasti\u00e3o Gon\u00e7alves Coelho 400, Divin\u00f3polis 35501-296, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1580-0644","authenticated-orcid":false,"given":"Jos\u00e9 Augusto Ferreira Perez","family":"Villar","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biochemistry, Universidade Federal de S\u00e3o Jo\u00e3o del Rei, Campus Centro-Oeste Dona Lindu, Avenida Sebasti\u00e3o Gon\u00e7alves Coelho 400, Divin\u00f3polis 35501-296, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4631-0130","authenticated-orcid":false,"given":"Leandro Augusto","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biochemistry, Universidade Federal de S\u00e3o Jo\u00e3o del Rei, Campus Centro-Oeste Dona Lindu, Avenida Sebasti\u00e3o Gon\u00e7alves Coelho 400, Divin\u00f3polis 35501-296, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8944-9415","authenticated-orcid":false,"given":"Eliana","family":"Barreto-Bergter","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria, Avenida Carlos Chagas Filho 373, Rio de Janeiro 21941-590, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0474-8388","authenticated-orcid":false,"given":"Ant\u00f4nio","family":"Ferreira-Pereira","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de G\u00f3es, Centro de Ci\u00eancias da Sa\u00fade, Universidade Federal do Rio de Janeiro, Cidade Universit\u00e1ria, Avenida Carlos Chagas Filho 373, Rio de Janeiro 21941-590, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"541340","DOI":"10.1155\/2014\/541340","article-title":"Multidrug resistance: An emerging crisis","volume":"2014","author":"Tanwar","year":"2014","journal-title":"Interdiscip. 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