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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...

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Detalles Bibliográficos
Autores principales: Zhu, Pan, Yue, Chaoping, Zeng, Xin, Chen, Xiulai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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