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Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function
A limited number of antifungal drugs, the side-effect of clinical drugs and the emergence of resistance create an urgent need for new antifungal treatment agents. High-throughput drug screening and in-depth drug action mechanism analyzation are needed to address this problem. In this study, we ident...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598568/ https://www.ncbi.nlm.nih.gov/pubmed/36290580 http://dx.doi.org/10.3390/antiox11101855 |
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author | Zhu, Pan Yue, Chaoping Zeng, Xin Chen, Xiulai |
author_facet | Zhu, Pan Yue, Chaoping Zeng, Xin Chen, Xiulai |
author_sort | Zhu, Pan |
collection | PubMed |
description | A limited number of antifungal drugs, the side-effect of clinical drugs and the emergence of resistance create an urgent need for new antifungal treatment agents. High-throughput drug screening and in-depth drug action mechanism analyzation are needed to address this problem. In this study, we identified that artemisinin and its derivatives possessed antifungal activity through a high-throughput screening of the FDA-approved drug library. Subsequently, drug-resistant strains construction, a molecular dynamics simulation and a transcription level analysis were used to investigate artemisinin’s action mechanism in Candida glabrata. Transcription factor pleiotropic drug resistance 1 (PDR1) was an important determinant of artemisinin’s sensitivity by regulating the drug efflux pump and ergosterol biosynthesis pathway, leading to mitochondrial dysfunction. This dysfunction was shown by a depolarization of the mitochondrial membrane potential, an enhancement of the mitochondrial membrane viscosity and an upregulation of the intracellular ROS level in fungi. The discovery shed new light on the development of antifungal agents and understanding artemisinin’s action mechanism. |
format | Online Article Text |
id | pubmed-9598568 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95985682022-10-27 Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function Zhu, Pan Yue, Chaoping Zeng, Xin Chen, Xiulai Antioxidants (Basel) Article A limited number of antifungal drugs, the side-effect of clinical drugs and the emergence of resistance create an urgent need for new antifungal treatment agents. High-throughput drug screening and in-depth drug action mechanism analyzation are needed to address this problem. In this study, we identified that artemisinin and its derivatives possessed antifungal activity through a high-throughput screening of the FDA-approved drug library. Subsequently, drug-resistant strains construction, a molecular dynamics simulation and a transcription level analysis were used to investigate artemisinin’s action mechanism in Candida glabrata. Transcription factor pleiotropic drug resistance 1 (PDR1) was an important determinant of artemisinin’s sensitivity by regulating the drug efflux pump and ergosterol biosynthesis pathway, leading to mitochondrial dysfunction. This dysfunction was shown by a depolarization of the mitochondrial membrane potential, an enhancement of the mitochondrial membrane viscosity and an upregulation of the intracellular ROS level in fungi. The discovery shed new light on the development of antifungal agents and understanding artemisinin’s action mechanism. MDPI 2022-09-20 /pmc/articles/PMC9598568/ /pubmed/36290580 http://dx.doi.org/10.3390/antiox11101855 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhu, Pan Yue, Chaoping Zeng, Xin Chen, Xiulai Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function |
title | Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function |
title_full | Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function |
title_fullStr | Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function |
title_full_unstemmed | Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function |
title_short | Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function |
title_sort | artemisinin targets transcription factor pdr1 and impairs candida glabrata mitochondrial function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598568/ https://www.ncbi.nlm.nih.gov/pubmed/36290580 http://dx.doi.org/10.3390/antiox11101855 |
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