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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...

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Autores principales: Li, Liping, Zhang, Teng, Xu, Jianrong, Wu, Jing, Wang, Yida, Qiu, Xiran, Zhang, Yu, Hou, Weitong, Yan, Lan, An, Maomao, Jiang, Yuanying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
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.
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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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