<i>Candida glabrata PDR1</i>
            , a Transcriptional Regulator of a Pleiotropic Drug Resistance Network, Mediates Azole Resistance in Clinical Isolates and Petite Mutants

Tsai, Huei Fung; Król, Anna; Sarti, Kelly E.; Bennett, John E.

doi:10.1128/aac.50.4.1384-1392.2006

Cited by 216 publications

(280 citation statements)

References 44 publications

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“…These five genes, CgCDR1, CgCDR2, and CgSNQ2, CgPDR1 and CgERG11, code for plasma membrane ATP-binding cassette transporters, zinc finger transcriptional regulator of pleiotropic drug resistance genes, and lanosterol 14-␣-demethylase (target of fluconazole), respectively (7,9,11,12). Consistent with earlier reports, wildtype cells responded to fluconazole exposure by elevating the expression of genes coding for drug transporters (Cdr1 and Cdr2) by 4 -6-fold (Fig.…”

Section: Cgbem2 Is Required For Activation Of Multidrug Efflux Pumps supporting

confidence: 76%

“…CgCDR1, CgCDR2, and CgSNQ2 are under the transcriptional regulation of a Zn 2 Cys 6 zinc cluster-containing transcription factor, CgPdr1 (12,13). CgPdr1 can directly bind to drugs and xenobiotics and stimulates drug efflux (14).…”

mentioning

confidence: 99%

“…CgPdr1 can directly bind to drugs and xenobiotics and stimulates drug efflux (14). Mutations in CgPdr1 rendering it hyperactive contribute to fluconazole resistance in clinical isolates (12,15).…”

mentioning

confidence: 99%

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The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

Borah¹,

Shivarathri

Kaur

2011

Journal of Biological Chemistry

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Invasive fungal infections are common clinical complications of neonates, critically ill, and immunocompromised patients worldwide. Candida species are the leading cause of disseminated fungal infections, with Candida albicans being the most prevalent species. Candida glabrata, the second/third most common cause of candidemia, shows reduced susceptibility to a widely used antifungal drug fluconazole. Here, we present findings from a screen of 9134 C. glabrata Tn7 insertion mutants for altered survival profiles in the presence of fluconazole. We have identified two components of RNA polymerase II mediator complex, three players of Rho GTPase-mediated signaling cascade, and two proteins implicated in actin cytoskeleton biogenesis and ergosterol biosynthesis that are required to sustain viability during fluconazole stress. We show that exposure to fluconazole leads to activation of the protein kinase C (PKC)-mediated cell wall integrity pathway in C. glabrata. Our data demonstrate that disruption of a RhoGAP (GTPase activating protein) domain-containing protein, CgBem2, results in budemergence defects, azole susceptibility, and constitutive activation of CgRho1-regulated CgPkc1 signaling cascade and cell wall-related phenotypes. The viability loss of Cgbem2⌬ mutant upon fluconazole treatment could be partially rescued by the PKC inhibitor staurosporine. Additionally, we present evidence that CgBEM2 is required for the transcriptional activation of genes encoding multidrug efflux pumps in response to fluconazole exposure. Last, we report that Hsp90 inhibitor geldanamycin renders fluconazole a fungicidal drug in C. glabrata.

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Section: Cgbem2 Is Required For Activation Of Multidrug Efflux Pumps supporting

confidence: 76%

mentioning

confidence: 99%

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The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

Borah¹,

Shivarathri

Kaur

2011

Journal of Biological Chemistry

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“…In this pathogenic yeast a single homologue of the budding yeast transcription factors Pdr1/Pdr3, CgPdr1, appears to control antifungal drug resistance through its action as an activator of all of the above mentioned ABC transporter encoding genes. This role is not only seen in the response of laboratory strains to suddenly imposed stress, but also in azole-resistant clinical isolates (Torelli et al 2008;Tsai et al 2006). The role of other C. glabrata CgPdr1 homologues, such as CgYrm1, has not been inspected so far.…”

Section: Cross-talk Between Multidrug Resistance Control and Oxidativmentioning

confidence: 99%

Complex Regulatory Interplay Between Multidrug Resistance and Oxidative Stress Response in Yeast: The FLR1 Regulatory Network as a Systems Biology Case-Study

Teixeira¹

2012

Oxidative Stress - Molecular Mechanisms and Biological Effects

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Oxidative Stress -Molecular Mechanisms and Biological Effects 324 chemical compounds, including widely used pesticides and pharmaceuticals, can induce oxidative stress indirectly, acting as pro-oxidant agents, at the same time that drug resistance mechanisms are activated. The comprehension of the underlying molecular mechanisms is, thus crucial to evaluate the toxicity of these xenobiotics and to design strategies to deal with the arising of multidrug resistance.Being now clear that these cellular protection programs, crucial to prevent or delay disease progression and ageing, are highly interconnected, it is pivotal to fully understand the underlying cross-mechanisms. Thus, this chapter integrates current knowledge of the link between oxidative stress and multidrug resistance transcriptional control in S. cerevisiae, extending it to pathogenic yeasts. The particular case of the regulation of the multidrug resistance transporter Flr1 is further explored as an example of the use of systems biology approaches, including the combination of experimental and computational techniques, to increase our understanding of complex regulatory networks, shedding light into the crosstalk between the MDR phenomenon and oxidative stress response.

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“…CgPdr1 binds to the PDRE consensus in CgCDR1 (Paul et al 2011). GOF mutations hyperactivate CgPdr1, resulting in up-regulation of target genes, including the ABC transporters involved in azole resistance (Vermitsky and Edlind 2004;Tsai et al 2006;Vermitsky et al 2006;Ferrari et al 2009;Caudle et al 2011). Fifty-eight distinct GOF mutations have been identified at 51 positions in CgPDR1 alleles from clinical azole-resistant isolates ).…”

Section: Trans-acting Elementsmentioning

confidence: 99%

Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

493

399

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Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug-resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

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Candida glabrata PDR1 , a Transcriptional Regulator of a Pleiotropic Drug Resistance Network, Mediates Azole Resistance in Clinical Isolates and Petite Mutants

Cited by 216 publications

References 44 publications

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

Complex Regulatory Interplay Between Multidrug Resistance and Oxidative Stress Response in Yeast: The FLR1 Regulatory Network as a Systems Biology Case-Study

Mechanisms of Antifungal Drug Resistance

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