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The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans
Candida albicans is the most common opportunistic fungal pathogen which can cause life-threatening bloodstream infections known as candidaemia. It is very important to discover new drugs and targets for the treatment of candidaemia. In this study, we first investigated the combination antifungal eff...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742966/ https://www.ncbi.nlm.nih.gov/pubmed/31555252 http://dx.doi.org/10.3389/fmicb.2019.02071 |
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author | Li, Liping Zhang, Teng Xu, Jianrong Wu, Jing Wang, Yida Qiu, Xiran Zhang, Yu Hou, Weitong Yan, Lan An, Maomao Jiang, Yuanying |
author_facet | Li, Liping Zhang, Teng Xu, Jianrong Wu, Jing Wang, Yida Qiu, Xiran Zhang, Yu Hou, Weitong Yan, Lan An, Maomao Jiang, Yuanying |
author_sort | Li, Liping |
collection | PubMed |
description | Candida albicans is the most common opportunistic fungal pathogen which can cause life-threatening bloodstream infections known as candidaemia. It is very important to discover new drugs and targets for the treatment of candidaemia. In this study, we first investigated the combination antifungal effects of the small molecule ENOblock and fluconazole (FLC) against FLC-resistant C. albicans. A checkerboard microdilution assay showed that ENOblock has a significant synergistic effect in combination with FLC against FLC-resistant C. albicans. The time-kill curve further confirmed the synergism of this compound with FLC against FLC-resistant C. albicans. Moreover, we demonstrated the significant inhibitory effects of ENOblock alone and in combination with FLC against C. albicans hypha and biofilm formation. Furthermore, the XTT assay showed that ENOblock has relatively low toxicity to human umbilical vein endothelial cells. The in vivo antifungal efficacy of ENOblock was further assessed in a murine model of systemic C. albicans infection. Although ENOblock alone was not sufficient to treat C. albicans infection, the combination of FLC and ENOblock showed significant in vivo activity against FLC-resistant C. albicans. Finally, using surface plasmon resonance analysis as well as an inhibition assay, we determined that ENOblock directly interacted with CaEno1 and significantly inhibited the transglutaminase activity of this enzyme, which is involved in the growth and morphogenesis of C. albicans. In summary, these results demonstrate the synergistic effects of FLC and ENOblock against FLC-resistant C. albicans, and indicate that inhibition of the transglutaminase activity of CaEno1 by ENOblock might confer an advantage for the synergism of FLC and ENOblock, suggesting the potential of ENOblock as a new antifungal candidate. |
format | Online Article Text |
id | pubmed-6742966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-67429662019-09-25 The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans Li, Liping Zhang, Teng Xu, Jianrong Wu, Jing Wang, Yida Qiu, Xiran Zhang, Yu Hou, Weitong Yan, Lan An, Maomao Jiang, Yuanying Front Microbiol Microbiology Candida albicans is the most common opportunistic fungal pathogen which can cause life-threatening bloodstream infections known as candidaemia. It is very important to discover new drugs and targets for the treatment of candidaemia. In this study, we first investigated the combination antifungal effects of the small molecule ENOblock and fluconazole (FLC) against FLC-resistant C. albicans. A checkerboard microdilution assay showed that ENOblock has a significant synergistic effect in combination with FLC against FLC-resistant C. albicans. The time-kill curve further confirmed the synergism of this compound with FLC against FLC-resistant C. albicans. Moreover, we demonstrated the significant inhibitory effects of ENOblock alone and in combination with FLC against C. albicans hypha and biofilm formation. Furthermore, the XTT assay showed that ENOblock has relatively low toxicity to human umbilical vein endothelial cells. The in vivo antifungal efficacy of ENOblock was further assessed in a murine model of systemic C. albicans infection. Although ENOblock alone was not sufficient to treat C. albicans infection, the combination of FLC and ENOblock showed significant in vivo activity against FLC-resistant C. albicans. Finally, using surface plasmon resonance analysis as well as an inhibition assay, we determined that ENOblock directly interacted with CaEno1 and significantly inhibited the transglutaminase activity of this enzyme, which is involved in the growth and morphogenesis of C. albicans. In summary, these results demonstrate the synergistic effects of FLC and ENOblock against FLC-resistant C. albicans, and indicate that inhibition of the transglutaminase activity of CaEno1 by ENOblock might confer an advantage for the synergism of FLC and ENOblock, suggesting the potential of ENOblock as a new antifungal candidate. Frontiers Media S.A. 2019-09-06 /pmc/articles/PMC6742966/ /pubmed/31555252 http://dx.doi.org/10.3389/fmicb.2019.02071 Text en Copyright © 2019 Li, Zhang, Xu, Wu, Wang, Qiu, Zhang, Hou, Yan, An and Jiang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Li, Liping Zhang, Teng Xu, Jianrong Wu, Jing Wang, Yida Qiu, Xiran Zhang, Yu Hou, Weitong Yan, Lan An, Maomao Jiang, Yuanying The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans |
title | The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans |
title_full | The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans |
title_fullStr | The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans |
title_full_unstemmed | The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans |
title_short | The Synergism of the Small Molecule ENOblock and Fluconazole Against Fluconazole-Resistant Candida albicans |
title_sort | synergism of the small molecule enoblock and fluconazole against fluconazole-resistant candida albicans |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742966/ https://www.ncbi.nlm.nih.gov/pubmed/31555252 http://dx.doi.org/10.3389/fmicb.2019.02071 |
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