scholarly journals Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae

Microbiology ◽  
2008 ◽  
Vol 154 (5) ◽  
pp. 1491-1501 ◽  
Author(s):  
Alix T. Coste ◽  
Mark Ramsdale ◽  
Françoise Ischer ◽  
Dominique Sanglard
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Pleiotropic Drug Resistance ◽  
Zinc Cluster

scholarly journals Membrane-active Compounds Activate the Transcription Factors Pdr1 and Pdr3 Connecting Pleiotropic Drug Resistance and Membrane Lipid Homeostasis in Saccharomyces cerevisiae

2007 ◽  
Vol 18 (12) ◽  
pp. 4932-4944 ◽  
Author(s):  
Christoph Schüller ◽  
Yasmine M. Mamnun ◽  
Hubert Wolfger ◽  
Nathan Rockwell ◽  
Jeremy Thorner ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Transcription Factors ◽  
Target Genes ◽  
Membrane Lipid ◽  
Yeast Cells ◽  
Dependent Manner ◽  
Pleiotropic Drug Resistance ◽  
Zinc Cluster ◽  
Genes Encoding

The Saccharomyces cerevisiae zinc cluster transcription factors Pdr1 and Pdr3 mediate general drug resistance to many cytotoxic substances also known as pleiotropic drug resistance (PDR). The regulatory mechanisms that activate Pdr1 and Pdr3 in response to the various xenobiotics are poorly understood. In this study, we report that exposure of yeast cells to 2,4-dichlorophenol (DCP), benzyl alcohol, nonionic detergents, and lysophospholipids causes rapid activation of Pdr1 and Pdr3. Furthermore, Pdr1/Pdr3 target genes encoding the ATP-binding cassette proteins Pdr5 and Pdr15 confer resistance against these compounds. Genome-wide transcript analysis of wild-type and pdr1Δ pdr3Δ cells treated with DCP reveals most prominently the activation of the PDR response but also other stress response pathways. Polyoxyethylene-9-laurylether treatment produced a similar profile with regard to activation of Pdr1 and Pdr3, suggesting activation of these by detergents. The Pdr1/Pdr3 response element is sufficient to confer regulation to a reporter gene by these substances in a Pdr1/Pdr3-dependent manner. Our data indicate that compounds with potential membrane-damaging or -perturbing effects might function as an activating signal for Pdr1 and Pdr3, and they suggest a role for their target genes in membrane lipid organization or remodeling.

scholarly journals Regulation of Efflux Pump Expression and Drug Resistance by the Transcription Factors Mrr1, Upc2, and Cap1 in Candida albicans

2011 ◽  
Vol 55 (5) ◽  
pp. 2212-2223 ◽  
Author(s):  
Sabrina Schubert ◽  
Katherine S. Barker ◽  
Sadri Znaidi ◽  
Sabrina Schneider ◽  
Franziska Dierolf ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Target Genes ◽  
Efflux Pump ◽  
Binding Studies ◽  
Gain Of Function ◽  
Content Type ◽  
Zinc Cluster ◽  
Constitutively Active

ABSTRACTConstitutive overexpression of the Mdr1 efflux pump is an important mechanism of acquired drug resistance in the yeastCandida albicans. The zinc cluster transcription factor Mrr1 is a central regulator ofMDR1expression, but other transcription factors have also been implicated inMDR1regulation. To better understand howMDR1-mediated drug resistance is achieved in this fungal pathogen, we studied the interdependence of Mrr1 and two otherMDR1regulators, Upc2 and Cap1, in the control ofMDR1expression. A mutated, constitutively active Mrr1 could upregulateMDR1and confer drug resistance in the absence of Upc2 or Cap1. On the other hand, Upc2 containing a gain-of-function mutation only slightly activated theMDR1promoter, and this activation depended on the presence of a functionalMRR1gene. In contrast, a C-terminally truncated, activated form of Cap1 could upregulateMDR1in a partially Mrr1-independent fashion. The induction ofMDR1expression by toxic chemicals occurred independently of Upc2 but required the presence of Mrr1 and also partially depended on Cap1. Transcriptional profiling andin vivoDNA binding studies showed that a constitutively active Mrr1 binds to and upregulates most of its direct target genes in the presence or absence of Cap1. Therefore, Mrr1 and Cap1 cooperate in the environmental induction ofMDR1expression in wild-typeC. albicans, but gain-of-function mutations in either of the two transcription factors can independently mediate efflux pump overexpression and drug resistance.

scholarly journals CaNdt80 Is Involved in Drug Resistance in Candida albicans by Regulating CDR1

2004 ◽  
Vol 48 (12) ◽  
pp. 4505-4512 ◽  
Author(s):  
Chia-Geun Chen ◽  
Yun-Liang Yang ◽  
Hsin-I Shih ◽  
Chia-Li Su ◽  
Hsiu-Jung Lo
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Type Strain ◽  
Antifungal Agents ◽  
Wild Type Strain ◽  
Efflux Pump ◽  
Antifungal Drugs ◽  
Galactosidase Activity ◽  
Wild Type

ABSTRACT Overexpression of CDR1, an efflux pump, is one of the major mechanisms contributing to drug resistance in Candida albicans. CDR1 p-lacZ was constructed and transformed into a Saccharomyces cerevisiae strain so that the lacZ gene could be used as the reporter to monitor the activity of the CDR1 promoter. Overexpression of CaNDT80, the C. albicans homolog of S. cerevisiae NDT80, increases the β-galactosidase activity of the CDR1 p-lacZ construct in S. cerevisiae. Furthermore, mutations in CaNDT80 abolish the induction of CDR1 expression by antifungal agents in C. albicans. Consistently, the Candt80/Candt80 mutant is also more susceptible to antifungal drugs than the wild-type strain. Thus, the gene for CaNdt80 may be the first gene among the regulatory factors involved in drug resistance in C. albicans whose function has been identified.

Pleiotropic drug-resistance attenuated genomic library improves elucidation of drug mechanisms

2015 ◽  
Vol 11 (11) ◽  
pp. 3129-3136 ◽  
Author(s):  
Namal V. C. Coorey ◽  
James H. Matthews ◽  
David S. Bellows ◽  
Paul H. Atkinson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Mechanism Of Action ◽  
Gene Deletion ◽  
Genomic Library ◽  
Deletion Mutants ◽  
Pleiotropic Drug Resistance ◽  
Genome Wide

Identifying Saccharomyces cerevisiae genome-wide gene deletion mutants that confer hypersensitivity to a xenobiotic aids the elucidation of its mechanism of action (MoA).

scholarly journals Genetic Architecture of Hsp90-Dependent Drug Resistance

2006 ◽  
Vol 5 (12) ◽  
pp. 2184-2188 ◽  
Author(s):  
Leah E. Cowen ◽  
Anne E. Carpenter ◽  
Oranart Matangkasombut ◽  
Gerald R. Fink ◽  
Susan Lindquist
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Genetic Architecture ◽  
Opportunistic Pathogen ◽  
Azole Resistance

ABSTRACT Hsp90 potentiates the evolution of azole resistance in the model yeast Saccharomyces cerevisiae and the opportunistic pathogen Candida albicans via calcineurin. Here, we explored effectors downstream of calcineurin regulating this Hsp90-dependent trait. Using S. cerevisiae erg3 mutants as a model, we determined that both Crz1 and Hph1 modulate azole resistance.

scholarly journals Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Christina Popp ◽  
Irene A. I. Hampe ◽  
Tobias Hertlein ◽  
Knut Ohlsen ◽  
P. David Rogers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Mouse Model ◽  
Ergosterol Biosynthesis ◽  
Fitness Costs ◽  
Content Type ◽  
Constitutive Overexpression ◽  
Fluconazole Resistant

ABSTRACT The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis. Resistance is often caused by gain-of-function mutations in the transcription factors Mrr1 and Tac1, which result in constitutive overexpression of multidrug efflux pumps, and Upc2, which result in constitutive overexpression of ergosterol biosynthesis genes. However, the deregulated gene expression that is caused by hyperactive forms of these transcription factors also reduces the fitness of the cells in the absence of the drug. To investigate whether fluconazole-resistant clinical C. albicans isolates have overcome the fitness costs of drug resistance, we assessed the relative fitness of C. albicans isolates containing resistance mutations in these transcription factors in competition with matched drug-susceptible isolates from the same patients. Most of the fluconazole-resistant isolates were outcompeted by the corresponding drug-susceptible isolates when grown in rich medium without fluconazole. On the other hand, some resistant isolates with gain-of-function mutations in MRR1 did not exhibit reduced fitness under these conditions. In a mouse model of disseminated candidiasis, three out of four tested fluconazole-resistant clinical isolates did not exhibit a significant fitness defect. However, all four fluconazole-resistant isolates were outcompeted by the matched susceptible isolates in a mouse model of gastrointestinal colonization, demonstrating that the effects of drug resistance on in vivo fitness depend on the host niche. Collectively, our results indicate that the fitness costs of drug resistance in C. albicans are not easily remediated, especially when proper control of gene expression is required for successful adaptation to life within a mammalian host.

Heterologous carotenoid production in Saccharomyces cerevisiae induces the pleiotropic drug resistance stress response

Yeast ◽  
2010 ◽  
Vol 27 (12) ◽  
pp. 983-998 ◽  
Author(s):  
René Verwaal ◽  
Yang Jiang ◽  
Jing Wang ◽  
Jean-Marc Daran ◽  
Gerhard Sandmann ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Stress Response ◽  
Pleiotropic Drug Resistance ◽  
Carotenoid Production

scholarly journals RPD3 and UME6 are involved in the activation of PDR5 transcription and pleiotropic drug resistance in ρ0 cells of Saccharomyces cerevisiae

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yoichi Yamada
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Positive Response ◽  
Mrna Levels ◽  
Transporter Gene ◽  
Transcriptional Expression ◽  
Pleiotropic Drug Resistance ◽  
Wild Type ◽  
Binding Partners ◽  
Retrograde Signalling

Abstract Background In Saccharomyces cerevisiae, the retrograde signalling pathway is activated in ρ0/− cells, which lack mitochondrial DNA. Within this pathway, the activation of the transcription factor Pdr3 induces transcription of the ATP-binding cassette (ABC) transporter gene, PDR5, and causes pleiotropic drug resistance (PDR). Although a histone deacetylase, Rpd3, is also required for cycloheximide resistance in ρ0/− cells, it is currently unknown whether Rpd3 and its DNA binding partners, Ume6 and Ash1, are involved in the activation of PDR5 transcription and PDR in ρ0/− cells. This study investigated the roles of RPD3, UME6, and ASH1 in the activation of PDR5 transcription and PDR by retrograde signalling in ρ0 cells. Results ρ0 cells in the rpd3∆ and ume6∆ strains, with the exception of the ash1∆ strain, were sensitive to fluconazole and cycloheximide. The PDR5 mRNA levels in ρ0 cells of the rpd3∆ and ume6∆ strains were significantly reduced compared to the wild-type and ash1∆ strain. Transcriptional expression of PDR5 was reduced in cycloheximide-exposed and unexposed ρ0 cells of the ume6∆ strain; the transcriptional positive response of PDR5 to cycloheximide exposure was also impaired in this strain. Conclusions RPD3 and UME6 are responsible for enhanced PDR5 mRNA levels and PDR by retrograde signalling in ρ0 cells of S. cerevisiae.

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