Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans
Candida infections have become a serious public health problem with high mortality rates, especially in immunocompromised patients, since Candida albicans is the major opportunistic pathogen responsible for systemic or invasive candidiasis. Commercially available antifungal agents are restricted and...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2019.02130/full |
| _version_ | 1818531057360699392 |
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| author | Isis Regina Grenier Capoci Karina Mayumi Sakita Daniella Renata Faria Franciele Abigail Vilugron Rodrigues-Vendramini Glaucia Sayuri Arita Admilton Gonçalves de Oliveira Maria Sueli Felipe Bernard Maigret Patricia de Souza Bonfim-Mendonça Erika Seki Kioshima Terezinha Inez Estivalet Svidzinski |
| author_facet | Isis Regina Grenier Capoci Karina Mayumi Sakita Daniella Renata Faria Franciele Abigail Vilugron Rodrigues-Vendramini Glaucia Sayuri Arita Admilton Gonçalves de Oliveira Maria Sueli Felipe Bernard Maigret Patricia de Souza Bonfim-Mendonça Erika Seki Kioshima Terezinha Inez Estivalet Svidzinski |
| author_sort | Isis Regina Grenier Capoci |
| collection | DOAJ |
| description | Candida infections have become a serious public health problem with high mortality rates, especially in immunocompromised patients, since Candida albicans is the major opportunistic pathogen responsible for systemic or invasive candidiasis. Commercially available antifungal agents are restricted and fungal resistance to such drugs has increased; therefore, the development of a more specific antifungal agent is necessary. Using assays for antifungal activity, here we report that two new compounds of 1,3,4-oxadiazoles class (LMM5 and LMM11), which were discovered by in silico methodologies as possible thioredoxin reductase inhibitors, were effective against C. albicans. Both compounds had in vitro antifungal activity with MIC 32 μg/ml. Cytotoxicity in vitro demonstrated that LMM5 and LMM11 were non-toxic in the cell lines evaluated. The kinetic of the time-kill curve suggested a fungistatic profile and showed an inhibitory effect of LMM5 and LMM11 in 12 h that remained for 24 and 36 h, which is better than fluconazole. In the murine systemic candidiasis model by C. albicans, the two compounds significantly reduced the renal and spleen fungal burden. According to the SEM and TEM images, we hypothesize that the mechanism of action of LMM5 and LMM11 is directly related to the inhibition of the enzyme thioredoxin reductase and internally affect the fungal cell. In view of all in vitro and in vivo results, LMM5 and LMM11 are effective therapeutic candidates for the development of new antifungal drugs addressing the treatment of human infections caused by C. albicans. |
| first_indexed | 2024-12-11T17:27:32Z |
| format | Article |
| id | doaj.art-c176f4da79964637b4b8702b0efc8c38 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-11T17:27:32Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-c176f4da79964637b4b8702b0efc8c382022-12-22T00:56:55ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2019-09-011010.3389/fmicb.2019.02130480810Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicansIsis Regina Grenier Capoci0Karina Mayumi Sakita1Daniella Renata Faria2Franciele Abigail Vilugron Rodrigues-Vendramini3Glaucia Sayuri Arita4Admilton Gonçalves de Oliveira5Maria Sueli Felipe6Bernard Maigret7Patricia de Souza Bonfim-Mendonça8Erika Seki Kioshima9Terezinha Inez Estivalet Svidzinski10Department of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilDepartment of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilDepartment of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilDepartment of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilDepartment of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilLaboratory of Electron Microscopy and Microanalysis, State University of Londrina, Londrina, BrazilDepartment of Cellular Biology, The University of Brasília, Brasília, BrazilLORIA, University of Lorraine, Nancy, FranceDepartment of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilDepartment of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilDepartment of Clinical Analysis and Biomedicine, The State University of Maringá, Maringá, BrazilCandida infections have become a serious public health problem with high mortality rates, especially in immunocompromised patients, since Candida albicans is the major opportunistic pathogen responsible for systemic or invasive candidiasis. Commercially available antifungal agents are restricted and fungal resistance to such drugs has increased; therefore, the development of a more specific antifungal agent is necessary. Using assays for antifungal activity, here we report that two new compounds of 1,3,4-oxadiazoles class (LMM5 and LMM11), which were discovered by in silico methodologies as possible thioredoxin reductase inhibitors, were effective against C. albicans. Both compounds had in vitro antifungal activity with MIC 32 μg/ml. Cytotoxicity in vitro demonstrated that LMM5 and LMM11 were non-toxic in the cell lines evaluated. The kinetic of the time-kill curve suggested a fungistatic profile and showed an inhibitory effect of LMM5 and LMM11 in 12 h that remained for 24 and 36 h, which is better than fluconazole. In the murine systemic candidiasis model by C. albicans, the two compounds significantly reduced the renal and spleen fungal burden. According to the SEM and TEM images, we hypothesize that the mechanism of action of LMM5 and LMM11 is directly related to the inhibition of the enzyme thioredoxin reductase and internally affect the fungal cell. In view of all in vitro and in vivo results, LMM5 and LMM11 are effective therapeutic candidates for the development of new antifungal drugs addressing the treatment of human infections caused by C. albicans.https://www.frontiersin.org/article/10.3389/fmicb.2019.02130/fullCandida albicansthioredoxin reductasein vitroin vivoantifungal activity |
| spellingShingle | Isis Regina Grenier Capoci Karina Mayumi Sakita Daniella Renata Faria Franciele Abigail Vilugron Rodrigues-Vendramini Glaucia Sayuri Arita Admilton Gonçalves de Oliveira Maria Sueli Felipe Bernard Maigret Patricia de Souza Bonfim-Mendonça Erika Seki Kioshima Terezinha Inez Estivalet Svidzinski Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans Frontiers in Microbiology Candida albicans thioredoxin reductase in vitro in vivo antifungal activity |
| title | Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans |
| title_full | Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans |
| title_fullStr | Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans |
| title_full_unstemmed | Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans |
| title_short | Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans |
| title_sort | two new 1 3 4 oxadiazoles with effective antifungal activity against candida albicans |
| topic | Candida albicans thioredoxin reductase in vitro in vivo antifungal activity |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2019.02130/full |
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