Dataset Information

Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function.

ABSTRACT: 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.

SUBMITTER: Zhu P

PROVIDER: S-EPMC9598568 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Artemisinin Targets Transcription Factor PDR1 and Impairs <i>Candida glabrata</i> Mitochondrial Function.

Zhu Pan P Yue Chaoping C Zeng Xin X Chen Xiulai X

Antioxidants (Basel, Switzerland) 20220920 10

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 mole ...[more]

PMID: 36290580

Similar Datasets

Project description:Fluconazole is one of the most commonly used antifungals today. A result of this has been the inevitable selection of fluconazole-resistant organisms. This is an especially acute problem in the pathogenic yeast Candida glabrata. Elevated minimal inhibitory concentrations for fluconazole in C. glabrata are frequently associated with substitution mutations within the Zn2Cys6 zinc cluster-containing transcription factor-encoding gene PDR1. These mutant Pdr1 regulators drive constitutively high expression of target genes like CDR1 that encodes an ATP-binding cassette transporter thought to act as a drug efflux pump. Exposure of C. glabrata to fluconazole induced expression of both Pdr1 and CDR1, although little is known of the molecular basis underlying the upstream signals that trigger Pdr1 activation. Here, we show that the protein phosphatase calcineurin is required for fluconazole-dependent induction of Pdr1 transcriptional regulation. Calcineurin catalytic activity is required for normal Pdr1 regulation, and a hyperactive form of this phosphatase can decrease susceptibility to the echinocandin caspofungin but does not show a similar change for fluconazole susceptibility. Loss of calcineurin from strains expressing two different gain-of-function forms of Pdr1 also caused a decrease in CDR1 expression and increased fluconazole susceptibility, demonstrating that even these hyperactive Pdr1 regulatory mutants cannot bypass the requirement for calcineurin. Our data implicate calcineurin activity as a link tying azole and echinocandin susceptibility together via the control of transcription factor activity.IMPORTANCEDrug-resistant microorganisms are a problem in the treatment of all infectious diseases; this is an especially acute problem with fungi due to the existence of only three major classes of antifungal drugs, including the azole drug fluconazole. In the pathogenic yeast Candida glabrata, mutant forms of a transcription factor called Pdr1 are commonly associated with decreased fluconazole susceptibility and poor clinical outcomes. Here, we identify a protein phosphatase called calcineurin that is required for fluconazole-dependent induction of Pdr1 transcriptional activation and associated drug susceptibility. Gain-of-function mutant forms of Pdr1 still required the presence of calcineurin to confer normally decreased fluconazole susceptibility. Previous studies showed that calcineurin controls susceptibility to the echinocandin class of antifungal drugs, and our data demonstrate that this protein phosphatase is also required for normal azole drug susceptibility. Calcineurin plays a central role in susceptibility to two of the three major classes of antifungal drugs in C. glabrata.

Dataset Information

Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function.

Publications

Artemisinin Targets Transcription Factor PDR1 and Impairs <i>Candida glabrata</i> Mitochondrial Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets