Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species
The rise in non-<i>albicans Candida</i> species, exhibiting unpredictable antifungal resistance, complicates treatment and contributes to the growing threat of invasive, life-threatening infections. This study evaluates the antifungal activity of four benzo[<i>a</i>]phenoxazi...
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2024-11-01
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| author | Maria Inês Pacheco Bárbara Guimarães Patrícia Pereira-Silva Augusto Costa-Barbosa M. Sameiro T. Gonçalves Maria João Sousa Paula Sampaio |
| author_facet | Maria Inês Pacheco Bárbara Guimarães Patrícia Pereira-Silva Augusto Costa-Barbosa M. Sameiro T. Gonçalves Maria João Sousa Paula Sampaio |
| author_sort | Maria Inês Pacheco |
| collection | DOAJ |
| description | The rise in non-<i>albicans Candida</i> species, exhibiting unpredictable antifungal resistance, complicates treatment and contributes to the growing threat of invasive, life-threatening infections. This study evaluates the antifungal activity of four benzo[<i>a</i>]phenoxazine derivatives (<b>C34</b>, <b>C35</b>, <b>A42</b>, and <b>A44</b>) against 14 <i>Candida</i> strains following EUCAST standards. Fluconazole interactions are analysed through fractional inhibitory concentration index (FICI) calculation and response surface analysis based on the Bliss model. Macrophage-like J774A.1 cells are used to assess <i>Candida</i> killing in the presence of synergistic compounds. The MIC values against the different strains vary, with <b>C34</b> showing the strongest activity, followed by <b>C35</b>, while <b>A42</b> has the highest MIC values, indicating lower efficacy. However, <b>A42</b> demonstrates the best synergy with fluconazole against fluconazole-resistant <i>Candida</i> strains. Cytotoxicity assays reveal that the chloropropyl group present in <b>C35</b> and <b>A42</b> enhances cytocompatibility. Co-culture with macrophages shows significant yeast killing for <i>C. albicans</i> and <i>C. auris</i> when fluconazole and <b>A42</b> are combined, requiring concentrations 4 and 16 times lower than their MIC values, enhancing antifungal activity. Given fluconazole’s fungistatic nature and the emergence of drug-resistant strains, benzo[<i>a</i>]phenoxazine derivatives’ ability to enhance fluconazole’s efficacy present a promising strategy to address antifungal resistance in critical pathogens. These findings align with global research priorities, offering new potential avenues for developing more effective antifungal therapies. |
| format | Article |
| id | doaj-art-d6c1fd7ce0334a1cbf432f0d4add3188 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj-art-d6c1fd7ce0334a1cbf432f0d4add31882025-08-20T02:49:56ZengMDPI AGMolecules1420-30492024-11-012921519710.3390/molecules29215197Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> SpeciesMaria Inês Pacheco0Bárbara Guimarães1Patrícia Pereira-Silva2Augusto Costa-Barbosa3M. Sameiro T. Gonçalves4Maria João Sousa5Paula Sampaio6Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCentre of Chemistry (CQUM), Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCentre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCentre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCentre of Chemistry (CQUM), Department of Chemistry, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCentre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCentre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalThe rise in non-<i>albicans Candida</i> species, exhibiting unpredictable antifungal resistance, complicates treatment and contributes to the growing threat of invasive, life-threatening infections. This study evaluates the antifungal activity of four benzo[<i>a</i>]phenoxazine derivatives (<b>C34</b>, <b>C35</b>, <b>A42</b>, and <b>A44</b>) against 14 <i>Candida</i> strains following EUCAST standards. Fluconazole interactions are analysed through fractional inhibitory concentration index (FICI) calculation and response surface analysis based on the Bliss model. Macrophage-like J774A.1 cells are used to assess <i>Candida</i> killing in the presence of synergistic compounds. The MIC values against the different strains vary, with <b>C34</b> showing the strongest activity, followed by <b>C35</b>, while <b>A42</b> has the highest MIC values, indicating lower efficacy. However, <b>A42</b> demonstrates the best synergy with fluconazole against fluconazole-resistant <i>Candida</i> strains. Cytotoxicity assays reveal that the chloropropyl group present in <b>C35</b> and <b>A42</b> enhances cytocompatibility. Co-culture with macrophages shows significant yeast killing for <i>C. albicans</i> and <i>C. auris</i> when fluconazole and <b>A42</b> are combined, requiring concentrations 4 and 16 times lower than their MIC values, enhancing antifungal activity. Given fluconazole’s fungistatic nature and the emergence of drug-resistant strains, benzo[<i>a</i>]phenoxazine derivatives’ ability to enhance fluconazole’s efficacy present a promising strategy to address antifungal resistance in critical pathogens. These findings align with global research priorities, offering new potential avenues for developing more effective antifungal therapies.https://www.mdpi.com/1420-3049/29/21/5197<i>Candida</i>benzo[<i>a</i>]phenoxazinesfluconazolesynergy |
| spellingShingle | Maria Inês Pacheco Bárbara Guimarães Patrícia Pereira-Silva Augusto Costa-Barbosa M. Sameiro T. Gonçalves Maria João Sousa Paula Sampaio Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species Molecules <i>Candida</i> benzo[<i>a</i>]phenoxazines fluconazole synergy |
| title | Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species |
| title_full | Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species |
| title_fullStr | Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species |
| title_full_unstemmed | Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species |
| title_short | Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species |
| title_sort | combining fluconazole with benzo i a i phenoxazine derivatives as a promising strategy against fluconazole resistant i candida i species |
| topic | <i>Candida</i> benzo[<i>a</i>]phenoxazines fluconazole synergy |
| url | https://www.mdpi.com/1420-3049/29/21/5197 |
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