Maria Inês Pacheco, Bárbara Guimarães, Patrícia Pereira-Silva, Augusto Costa-Barbosa, M Sameiro T Gonçalves, Maria João Sousa, Paula Sampaio
{"title":"Combining Fluconazole with Benzo[<i>a</i>]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant <i>Candida</i> Species.","authors":"Maria Inês Pacheco, Bárbara Guimarães, Patrícia Pereira-Silva, Augusto Costa-Barbosa, M Sameiro T Gonçalves, Maria João Sousa, Paula Sampaio","doi":"10.3390/molecules29215197","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"29 21","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11547786/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecules","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.3390/molecules29215197","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The rise in non-albicans Candida 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[a]phenoxazine derivatives (C34, C35, A42, and A44) against 14 Candida 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 Candida killing in the presence of synergistic compounds. The MIC values against the different strains vary, with C34 showing the strongest activity, followed by C35, while A42 has the highest MIC values, indicating lower efficacy. However, A42 demonstrates the best synergy with fluconazole against fluconazole-resistant Candida strains. Cytotoxicity assays reveal that the chloropropyl group present in C35 and A42 enhances cytocompatibility. Co-culture with macrophages shows significant yeast killing for C. albicans and C. auris when fluconazole and A42 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[a]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.
期刊介绍:
Molecules (ISSN 1420-3049, CODEN: MOLEFW) is an open access journal of synthetic organic chemistry and natural product chemistry. All articles are peer-reviewed and published continously upon acceptance. Molecules is published by MDPI, Basel, Switzerland. Our aim is to encourage chemists to publish as much as possible their experimental detail, particularly synthetic procedures and characterization information. There is no restriction on the length of the experimental section. In addition, availability of compound samples is published and considered as important information. Authors are encouraged to register or deposit their chemical samples through the non-profit international organization Molecular Diversity Preservation International (MDPI). Molecules has been launched in 1996 to preserve and exploit molecular diversity of both, chemical information and chemical substances.