Chemosensitisation of drug-resistant and drug-sensitive yeast cells to antifungals

Cernicka, Jana; Kozovská, Zuzana; Hnatova, Martina; Valachovič, Martin; Hapala, Ivan; Riedl, Zsuzsanna; Hajós, György; Šubík, Július

doi:10.1016/j.ijantimicag.2006.08.037

Cited by 21 publications

(21 citation statements)

References 49 publications

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“…Nuclear petites generated by the deletion of QCR7, RIP1, and CYT1, encoding different subunits of respiratory chain complex III, and a homozygous deletion strain of QDR3 displaying a partial respiratory deficiency, as well as deletion strains of MIG1 and HAP4, encoding proteins which are involved in glucose repression and control of respiration, respectively, were included in this study. QDR3 encodes a multidrug transporter (37), and strains with this gene deleted display partial respiratory deficiency (data not shown); PDR3 encodes a protein whose sole function is drug/ chemical transport and regulation of these transport processes (8,25,26,31). The respiration-sufficient mutant pdr3⌬/pdr3⌬ was included as a control strain with respect to the partially respiration-deficient qdr3⌬/qdr3⌬ mutant.…”

Section: Resultsmentioning

confidence: 99%

Integration of Metabolic Modeling and Phenotypic Data in Evaluation and Improvement of Ethanol Production Using Respiration-Deficient Mutants of Saccharomyces cerevisiae

Dikicioglu

Pir

Önsan

et al. 2008

Appl Environ Microbiol

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Flux balance analysis and phenotypic data were used to provide clues to the relationships between the activities of gene products and the phenotypes resulting from the deletion of genes involved in respiratory function in Saccharomyces cerevisiae. The effect of partial or complete respiratory deficiency on the ethanol production and growth characteristics of hap4⌬/hap4⌬, mig1⌬/mig1⌬, qdr3⌬/qdr3⌬, pdr3⌬/pdr3⌬, qcr7⌬/ qcr7⌬, cyt1⌬/cyt1⌬, and rip1⌬/rip1⌬ mutants grown in microaerated chemostats was investigated. The study provided additional evidence for the importance of the selection of a physiologically relevant objective function, and it may improve quantitative predictions of exchange fluxes, as well as qualitative estimations of changes in intracellular fluxes. Ethanol production was successfully predicted by flux balance analysis in the case of the qdr3⌬/qdr3⌬ mutant, with maximization of ethanol production as the objective function, suggesting an additional role for Qdr3p in respiration. The absence of similar changes in estimated intracellular fluxes in the qcr7⌬/qcr7⌬ mutant compared to the rip1⌬/rip1⌬ and cyt1⌬/cyt1⌬ mutants indicated that the effect of the deletion of this subunit of complex III was somehow compensated for. Analysis of predicted flux distributions indicated self-organization of intracellular fluxes to avoid NAD ؉ /NADH imbalance in rip1⌬/rip1⌬ and cyt1⌬/ cyt1⌬ mutants, but not the qcr7⌬/qcr7⌬ mutant. The flux through the glycerol efflux channel, Fps1p, was estimated to be zero in all strains under the investigated conditions. This indicates that previous strategies for improving ethanol production, such as the overexpression of the glutamate synthase gene GLT1 in a GDH1 deletion background or deletion of the glycerol efflux channel gene FPS1 and overexpression of GLT1, are unnecessary in a respiration-deficient background.

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Section: Resultsmentioning

confidence: 99%

Integration of Metabolic Modeling and Phenotypic Data in Evaluation and Improvement of Ethanol Production Using Respiration-Deficient Mutants of Saccharomyces cerevisiae

Dikicioglu

Pir

Önsan

et al. 2008

Appl Environ Microbiol

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“…In addition, the incidence of mycoses caused by opportunistic fungi is rising [1]. CTBT, 7-chlorotetrazolo [5,1-c]benzo[1,2,4]triazine, has antifungal activity and enhances the efficacy of other antifungals with different targets such as cycloheximide, fluconazole or 5-fluorocytosine [2]. The molecular mechanism of CTBT action has not yet been resolved.…”

Section: Introductionmentioning

confidence: 99%

Chemogenomic and transcriptome analysis identifies mode of action of the chemosensitizing agent CTBT (7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine)

et al. 2010

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BackgroundCTBT (7-chlorotetrazolo [5,1-c]benzo[1,2,4]triazine) increases efficacy of commonly used antifungal agents by an unknown mechanism. It increases the susceptibility of Saccharomyces cerevisiae, Candida albicans and Candida glabrata cells to cycloheximide, 5-fluorocytosine and azole antimycotic drugs. Here we elucidate CTBT mode of action with a combination of systematic genetic and transcriptome analysis.ResultsTo identify the cellular processes affected by CTBT, we screened the systematic haploid deletion mutant collection for CTBT sensitive mutants. We identified 169 hypersensitive deletion mutants. The deleted genes encode proteins mainly involved in mitochondrial functions, DNA repair, transcription and chromatin remodeling, and oxidative stress response. We found that the susceptibility of yeast cells to CTBT depends on molecular oxygen. Transcriptome analysis of the immediate early response to CTBT revealed rapid induction of oxidant and stress response defense genes. Many of these genes depend on the transcription factors Yap1 and Cin5. Yap1 accumulates rapidly in the nucleus in CTBT treated cells suggesting acute oxidative stress. Moreover, molecular calculations supported a superoxide generating activity of CTBT. Superoxide production in vivo by CTBT was found associated to mitochondria as indicated by oxidation of MitoSOX Red.ConclusionWe conclude that CTBT causes intracellular superoxide production and oxidative stress in fungal cells and is thus enhancing antimycotic drug effects by a secondary stress.

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“…This compound has antifungal activity and enhances the efficacy of other antifungals, such as cycloheximide, fluconazole or 5-fluorocytosine. Its exact mode of action is not well understood, but it was shown that it causes oxidative stress in the cell with the damage of mitochondria and DNA [123]. Some oligopeptides also reverse multidrug resistance, for example FKCRRWQWRM (Pep2), which enhances itraconazole efficacy by increasing ATP leakage from the cell [124].…”

Section: Modulation Of Multidrug Abc Transportersmentioning

confidence: 99%

Yeast ABC proteins involved in multidrug resistance

Piecuch¹,

Obłąk²

2014

Cellular and Molecular Biology Letters

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Pleiotropic drug resistance is a complex phenomenon that involves many proteins that together create a network. One of the common mechanisms of multidrug resistance in eukaryotic cells is the active efflux of a broad range of xenobiotics through ATP-binding cassette (ABC) transporters. Saccharomyces cerevisiae is often used as a model to study such activity because of the functional and structural similarities of its ABC transporters to mammalian ones. Numerous ABC transporters are found in humans and some are associated with the resistance of tumors to chemotherapeutics. Efflux pump modulators that change the activity of ABC proteins are the most promising candidate drugs to overcome such resistance. These modulators can be chemically synthesized or isolated from natural sources (e.g., plant alkaloids) and might also be used in the treatment of fungal infections. There are several generations of synthetic modulators that differ in specificity, toxicity and effectiveness, and are often used for other clinical effects.

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Chemosensitisation of drug-resistant and drug-sensitive yeast cells to antifungals

Cited by 21 publications

References 49 publications

Integration of Metabolic Modeling and Phenotypic Data in Evaluation and Improvement of Ethanol Production Using Respiration-Deficient Mutants of Saccharomyces cerevisiae

Integration of Metabolic Modeling and Phenotypic Data in Evaluation and Improvement of Ethanol Production Using Respiration-Deficient Mutants of Saccharomyces cerevisiae

Chemogenomic and transcriptome analysis identifies mode of action of the chemosensitizing agent CTBT (7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine)

Yeast ABC proteins involved in multidrug resistance

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