Cyclic AMP Signaling Pathway Modulates Susceptibility of
            <i>Candida</i>
            Species and
            <i>Saccharomyces cerevisiae</i>
            to Antifungal Azoles and Other Sterol Biosynthesis Inhibitors

Jain, Pooja; Akula, Indira; Edlind, Thomas D.

doi:10.1128/aac.47.10.3195-3201.2003

Cited by 74 publications

(60 citation statements)

References 39 publications

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“…In the present study, we aimed to further unravel the molecular basis of reduced susceptibility or increased tolerance of C. albicans biofilm cells to miconazole. To this end, we determined the miconazole sensitivity of biofilms of C. albicans mutants affected in cyclic AMP signalling, as it was previously reported that the cAMP signalling pathway is involved in the tolerance of planktonic C. albicans cells to miconazole (Jain et al, 2003). In addition, we validated the obtained in vitro data in an in vivo biofilm model, in which we administered miconazole intraperitoneally to rats (Ricicová et al, 2010).…”

Section: Introductionmentioning

confidence: 57%

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

Bink

Govaert

Vandenbosch

et al. 2012

Journal of Medical Microbiology

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We investigated the molecular basis of the tolerance of Candida albicans biofilms to antifungals using the miconazole as a model compound, and translated the resulting data to other antifungals. Sessile cells of C. albicans Defg1, lacking the transcription factor Efg1, showed increased susceptibility to miconazole, amphotericin B and caspofungin, whereas these sessile cells were equally resistant to fluconazole. The increased sensitivity to miconazole was, at least, partly due to an increased accumulation of miconazole in the cells as compared to wild-type or reintegrant Defg1(EFG1) sessile cells. By using a rat biofilm model, we further confirmed the role of Efg1 in the tolerance of C. albicans biofilms to miconazole when grown in vivo.

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Section: Introductionmentioning

confidence: 57%

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

Bink

Govaert

Vandenbosch

et al. 2012

Journal of Medical Microbiology

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“…In yeast, Ras activation leads to cAMP production and activation of protein kinase A. A link between cAMP-PKA signaling pathway and miconazole sensitivity in yeast has previously been reported (14); it was demonstrated that yeast mutants affected in cAMP-PKA signaling were hypersensitive toward miconazole and the observed miconazole hypersensitivity of these mutants could be partially restored by exogenous addition of cAMP (14). Whether miconazole activates Ras signaling in yeast, resulting in elevated cAMP levels and ROS levels via actin-mediated mitochondrial dysfunction, needs to be investigated further.…”

Section: Discussionmentioning

confidence: 99%

“…In this respect, yeast mutants affected in genes involved in DNA synthesis and repair, transcription, and chromatin structure (including ADA/Spt-Ada-Gcn5-acetyltransferase (SAGA) histone acetyltransferase complexes or SWI/SNF nucleosome remodeling complex) were previously identified as hypersensitive to a variety of stresses, including oxidative and chemical stress (14,15,16). This finding highlights the requirement for de novo transcription in response to environmental stress.…”

Section: Discussionmentioning

confidence: 99%

Miconazole Induces Changes in Actin Cytoskeleton prior to Reactive Oxygen Species Induction in Yeast

Thevissen

Ayscough

Aerts

et al. 2007

Journal of Biological Chemistry

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The antifungal compound miconazole inhibits ergosterol biosynthesis and induces reactive oxygen species (ROS) in susceptible yeast species. To further uncover the mechanism of miconazole antifungal action and tolerance mechanisms, we screened the complete set of haploid Saccharomyces cerevisiae gene deletion mutants for mutants with an altered miconazole sensitivity phenotype. We identified 29 S. cerevisiae genes, which when deleted conferred at least 4-fold hypersensitivity to miconazole. Major functional groups encode proteins involved in tryptophan biosynthesis, membrane trafficking including endocytosis, regulation of actin cytoskeleton, and gene expression. With respect to the antifungal activity of miconazole, we demonstrate an antagonism with tryptophan and a synergy with a yeast endocytosis inhibitor. Because actin dynamics and induction of ROS are linked in yeast, we further focused on miconazole-mediated changes in actin cytoskeleton organization. In this respect, we demonstrate that miconazole induces changes in the actin cytoskeleton, indicative of increased filament stability, prior to ROS induction. These data provide novel mechanistic insights in the mode of action of a ROS-inducing azole.Miconazole belongs to the azole antifungals, which are currently the most widely used antimycotics. Azoles inhibit ergosterol biosynthesis, resulting in accumulation of toxic methylated sterol intermediates and, subsequently, fungal cell growth arrest (1). Recently, an additional mode of antifungal action was uncovered for miconazole. Apart from inhibition of ergosterol biosynthesis, miconazole induces reactive oxygen species (ROS) 6 in susceptible fungi, leading to fungal cell death (2, 3).The aim of the present study was to further unravel the mode of antifungal action of miconazole and tolerance mechanisms against miconazole in yeast. Information regarding drug tolerance mechanisms is invaluable for antifungal therapy: theoretically, miconazole action can be increased by using inhibitors of identified yeast tolerance mechanisms. To our knowledge, this study is the first report on yeast tolerance mechanisms against imidazoles, such as miconazole, and their mode of action using a genome-wide screening approach in yeast. In this study, we screened the haploid set of Saccharomyces cerevisiae deletion mutants in non-essential genes for both hypersensitivity and resistance to miconazole by determining the minimal inhibitory miconazole concentration (MIC) for all individual yeast knock-out mutants using 2-fold dilution series of miconazole in liquid YPD medium. In this way, no miconazole-resistant yeast mutants could be identified. However, we could identify 29 S. cerevisiae genes or open reading frames that upon deletion result in at least 4-fold hypersensitivity to miconazole and hence are involved in miconazole tolerance. The following major functional families of miconazole tolerance genes could be distinguished: (i) tryptophan biosynthesis, (ii) membrane trafficking, including endocytosis, (iii) regulation of ac...

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“…Inhibition of calcineurin-mediated calcium signaling augments the effect of azoles and makes them fungicidal in Saccharomyces cerevisiae, C. albicans, C. glabrata, and C. krusei (10,18,19). Additionally, C. albicans and S. cerevisiae mutants disrupted for genes involved in cyclic AMP/protein kinase A signaling pathway are hypersusceptible to fluconazole (20). Furthermore, genetic or chemical abrogation of function of a highly conserved chaperone Hsp90 leads to antifungal drug susceptibility in diverse fungi (21).…”

mentioning

confidence: 99%

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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Cyclic AMP Signaling Pathway Modulates Susceptibility of Candida Species and Saccharomyces cerevisiae to Antifungal Azoles and Other Sterol Biosynthesis Inhibitors

Cited by 74 publications

References 39 publications

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

Miconazole Induces Changes in Actin Cytoskeleton prior to Reactive Oxygen Species Induction in Yeast

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

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