The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model
Abstract Background Candida albicans is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in C. albicans. New...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | BMC Microbiology |
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| Online Access: | https://doi.org/10.1186/s12866-024-03181-z |
| _version_ | 1827328414366826496 |
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| author | Salwa E. Gomaa Hisham A. Abbas Fatma A. Mohamed Mohamed A. M. Ali Tarek M. Ibrahim Alyaa S. Abdel Halim Mashael A. Alghamdi Basem Mansour Anis Ahmad Chaudhary Amr Elkelish Fehmi Boufahja Wael A. H. Hegazy Fatma Al-zahraa A. Yehia |
| author_facet | Salwa E. Gomaa Hisham A. Abbas Fatma A. Mohamed Mohamed A. M. Ali Tarek M. Ibrahim Alyaa S. Abdel Halim Mashael A. Alghamdi Basem Mansour Anis Ahmad Chaudhary Amr Elkelish Fehmi Boufahja Wael A. H. Hegazy Fatma Al-zahraa A. Yehia |
| author_sort | Salwa E. Gomaa |
| collection | DOAJ |
| description | Abstract Background Candida albicans is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in C. albicans. New treatment approaches are needed to combat candidiasis especially in the dwindled supply of new effective and safe antifungals. The resistance to azoles is mainly attributed to export of azoles outside the cells by means of the efflux pump that confers cross resistance to all azoles including fluconazole (FLC). Objectives This study aimed to investigate the possible efflux pump inhibiting activity of fusidic acid (FA) in C. albicans resistant isolates and the potential use of Fusidic acid in combination with fluconazole to potentiate the antifungal activity of fluconazole to restore its activity in the resistant C. albicans isolates. Methods The resistance of C. albicans isolates was assessed by determination of minimum inhibitory concentration. The effect of Fusidic acid at sub-inhibitory concentration on efflux activity was assayed by rhodamine 6G efflux assay and intracellular accumulation. Mice model studies were conducted to evaluate the anti-efflux activity of Fusidic acid and its synergistic effects in combination with fluconazole. Impact of Fusidic acid on ergosterol biosynthesis was quantified. The synergy of fluconazole when combined with Fusidic acid was investigated by determination of minimum inhibitory concentration. The cytotoxicity of Fusidic acid was tested against erythrocytes. The effect of Fusidic acid on efflux pumps was tested at the molecular level by real-time PCR and in silico study. In vivo vulvovaginitis mice model was used to confirm the activity of the combination in treating vulvovaginal candidiasis. Results Fusidic acid showed efflux inhibiting activity as it increased the accumulation of rhodamine 6G, a substrate for ABC-efflux transporter, and decreased its efflux in C. albicans cells. The antifungal activity of fluconazole was synergized when combined with Fusidic acid. Fusidic acid exerted only minimal cytotoxicity on human erythrocytes indicating its safety. The FA efflux inhibitory activity could be owed to its ability to interfere with efflux protein transporters as revealed by docking studies and downregulation of the efflux-encoding genes of both ABC transporters and MFS superfamily. Moreover, in vivo mice model showed that using fluconazole-fusidic acid combination by vaginal route enhanced fluconazole antifungal activity as shown by lowered fungal burden and a negligible histopathological change in vaginal tissue. Conclusion The current findings highlight FA’s potential as a potential adjuvant to FLC in the treatment of vulvovaginal candidiasis. |
| first_indexed | 2024-03-07T15:17:35Z |
| format | Article |
| id | doaj.art-f0458765cdb941ff83feee4efdffab8c |
| institution | Directory Open Access Journal |
| issn | 1471-2180 |
| language | English |
| last_indexed | 2024-03-07T15:17:35Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Microbiology |
| spelling | doaj.art-f0458765cdb941ff83feee4efdffab8c2024-03-05T17:51:38ZengBMCBMC Microbiology1471-21802024-02-0124111610.1186/s12866-024-03181-zThe anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse modelSalwa E. Gomaa0Hisham A. Abbas1Fatma A. Mohamed2Mohamed A. M. Ali3Tarek M. Ibrahim4Alyaa S. Abdel Halim5Mashael A. Alghamdi6Basem Mansour7Anis Ahmad Chaudhary8Amr Elkelish9Fehmi Boufahja10Wael A. H. Hegazy11Fatma Al-zahraa A. Yehia12Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig UniversityDepartment of Microbiology and Immunology, Faculty of Pharmacy, Zagazig UniversityDepartment of Microbiology and Immunology, Faculty of Pharmacy, Zagazig UniversityDepartment of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU)Department of Pharmaceutics, Faculty of Pharmacy, Zagazig UniversityDepartment of Biochemistry, Faculty of Science, Ain Shams UniversityDepartment of Chemistry, Imam Mohammad Ibn Saud Islamic University (IMSIU)Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and TechnologyDepartment of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU)Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU)Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU)Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig UniversityDepartment of Microbiology and Immunology, Faculty of Pharmacy, Zagazig UniversityAbstract Background Candida albicans is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in C. albicans. New treatment approaches are needed to combat candidiasis especially in the dwindled supply of new effective and safe antifungals. The resistance to azoles is mainly attributed to export of azoles outside the cells by means of the efflux pump that confers cross resistance to all azoles including fluconazole (FLC). Objectives This study aimed to investigate the possible efflux pump inhibiting activity of fusidic acid (FA) in C. albicans resistant isolates and the potential use of Fusidic acid in combination with fluconazole to potentiate the antifungal activity of fluconazole to restore its activity in the resistant C. albicans isolates. Methods The resistance of C. albicans isolates was assessed by determination of minimum inhibitory concentration. The effect of Fusidic acid at sub-inhibitory concentration on efflux activity was assayed by rhodamine 6G efflux assay and intracellular accumulation. Mice model studies were conducted to evaluate the anti-efflux activity of Fusidic acid and its synergistic effects in combination with fluconazole. Impact of Fusidic acid on ergosterol biosynthesis was quantified. The synergy of fluconazole when combined with Fusidic acid was investigated by determination of minimum inhibitory concentration. The cytotoxicity of Fusidic acid was tested against erythrocytes. The effect of Fusidic acid on efflux pumps was tested at the molecular level by real-time PCR and in silico study. In vivo vulvovaginitis mice model was used to confirm the activity of the combination in treating vulvovaginal candidiasis. Results Fusidic acid showed efflux inhibiting activity as it increased the accumulation of rhodamine 6G, a substrate for ABC-efflux transporter, and decreased its efflux in C. albicans cells. The antifungal activity of fluconazole was synergized when combined with Fusidic acid. Fusidic acid exerted only minimal cytotoxicity on human erythrocytes indicating its safety. The FA efflux inhibitory activity could be owed to its ability to interfere with efflux protein transporters as revealed by docking studies and downregulation of the efflux-encoding genes of both ABC transporters and MFS superfamily. Moreover, in vivo mice model showed that using fluconazole-fusidic acid combination by vaginal route enhanced fluconazole antifungal activity as shown by lowered fungal burden and a negligible histopathological change in vaginal tissue. Conclusion The current findings highlight FA’s potential as a potential adjuvant to FLC in the treatment of vulvovaginal candidiasis.https://doi.org/10.1186/s12866-024-03181-zDrug repurposingVaginal candidiasisFluconazole resistant Candida albicansFusidic acidEfflux pumps |
| spellingShingle | Salwa E. Gomaa Hisham A. Abbas Fatma A. Mohamed Mohamed A. M. Ali Tarek M. Ibrahim Alyaa S. Abdel Halim Mashael A. Alghamdi Basem Mansour Anis Ahmad Chaudhary Amr Elkelish Fehmi Boufahja Wael A. H. Hegazy Fatma Al-zahraa A. Yehia The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model BMC Microbiology Drug repurposing Vaginal candidiasis Fluconazole resistant Candida albicans Fusidic acid Efflux pumps |
| title | The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model |
| title_full | The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model |
| title_fullStr | The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model |
| title_full_unstemmed | The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model |
| title_short | The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model |
| title_sort | anti staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model |
| topic | Drug repurposing Vaginal candidiasis Fluconazole resistant Candida albicans Fusidic acid Efflux pumps |
| url | https://doi.org/10.1186/s12866-024-03181-z |
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