Responses of Pathogenic and Nonpathogenic Yeast Species to Steroids Reveal the Functioning and Evolution of Multidrug Resistance Transcriptional Networks

Banerjee, Dibyendu; Lelandais, Gaëlle; Shukla, Sudhanshu; Mukhopadhyay, Gauranga; Jacq, Claude; Devaux, Frédéric; Prasad, Rajendra

doi:10.1128/ec.00256-07

Cited by 37 publications

(37 citation statements)

References 41 publications

(57 reference statements)

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“…It is interesting that MG treatment led not only to the detection of the convergence of the UPC2 and STP2 regulatory pathways but also to the identification of new targets. While analyzing the transcriptional response to progesterone as the best inducer of MDR in C. albicans, we could identify new TAC1-regulated targets, which were not detected by fluphenazine, one of the best inducers of MDR (2). Thus, the fungicidal activity of MG against C. albicans not only provides an opportunity for its application as a potential antifungal but can also aid in the identification of new regulatory circuits regulating MDR.…”

Section: Discussionmentioning

confidence: 93%

In VitroEffect of Malachite Green on Candida albicans Involves Multiple Pathways and Transcriptional RegulatorsUPC2andSTP2

Dhamgaye

Devaux

Manoharlal

et al. 2012

Antimicrob Agents Chemother

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In this study, we show that a chemical dye, malachite green (MG), which is commonly used in the fish industry as an antifungal, antiparasitic, and antibacterial agent, could effectively kill Candida albicans and non-C. albicans species. We have demonstrated that Candida cells are susceptible to MG at a very low concentration (MIC that reduces growth by 50% [MIC 50 ], 100 ng ml ؊1 ) and that the effect of MG is independent of known antifungal targets, such as ergosterol metabolism and major drug efflux pump proteins. Transcriptional profiling in response to MG treatment of C. albicans cells revealed that of a total of 207 responsive genes, 167 genes involved in oxidative stress, virulence, carbohydrate metabolism, heat shock, amino acid metabolism, etc., were upregulated, while 37 genes involved in iron acquisition, filamentous growth, mitochondrial respiration, etc., were downregulated. We confirmed experimentally that Candida cells exposed to MG resort to a fermentative mode of metabolism, perhaps due to defective respiration. In addition, we showed that MG triggers depletion of intracellular iron pools and enhances reactive oxygen species (ROS) levels. These effects could be reversed by the addition of iron or antioxidants, respectively. We provided evidence that the antifungal effect of MG is exerted through the transcription regulators UPC2 (regulating ergosterol biosynthesis and azole resistance) and STP2 (regulating amino acid permease genes). Taken together, our transcriptome, genetic, and biochemical results allowed us to decipher the multiple mechanisms by which MG exerts its anti-Candida effects, leading to a metabolic shift toward fermentation, increased generation of ROS, labile iron deprivation, and cell necrosis.

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Section: Discussionmentioning

confidence: 93%

In VitroEffect of Malachite Green on Candida albicans Involves Multiple Pathways and Transcriptional RegulatorsUPC2andSTP2

Dhamgaye

Devaux

Manoharlal

et al. 2012

Antimicrob Agents Chemother

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“…RNA isolation was done by following the TRIzol (Sigma) method according to the manufacturer's specifications, except that 300 l acid-washed 0.4-to 0.6-mm glass beads (Sigma, St. Louis, MO, USA) was used during cell lysis (14). Ten milligrams of purified total RNA was used to synthesize cDNA by using the protocol described previously (www.transcriptome.ens.fr /sgdb/protocols/labeling.yeast.php).…”

Section: Methodsmentioning

confidence: 99%

Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans

Kumar

Dhamgaye

Maurya

et al. 2014

Antimicrob Agents Chemother

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Curcumin (CUR) shows antifungal activity against a range of pathogenic fungi, including Candida albicans. The reported mechanisms of action of CUR include reactive oxygen species (ROS) generation, defects in the ergosterol biosynthesis pathway, decrease in hyphal development, and modulation of multidrug efflux pumps. Reportedly, each of these pathways is independently linked to the cell wall machinery in C. albicans, but surprisingly, CUR has not been previously implicated in cell wall damage. In the present study, we performed transcriptional profiling to identify the yet-unidentified targets of CUR in C. albicans. We found that, among 348 CUR-affected genes, 51 were upregulated and 297 were downregulated. Interestingly, most of the cell wall integrity pathway genes were downregulated. The possibility of the cell wall playing a critical role in the mechanism of CUR required further validation; therefore, we performed specific experiments to establish if there was any link between the two. The fractional inhibitory concentration index values of 0.24 to 0.37 show that CUR interacts synergistically with cell wall-perturbing (CWP) agents (caspofungin, calcofluor white, Congo red, and SDS). Furthermore, we could observe cell wall damage and membrane permeabilization by CUR alone, as well as synergistically with CWP agents. We also found hypersusceptibility in calcineurin and mitogen-activated protein (MAP) kinase pathway mutants against CUR, which confirmed that CUR also targets cell wall biosynthesis in C. albicans. Together, these data provide strong evidence that CUR disrupts cell wall integrity in C. albicans. This new information on the mechanistic action of CUR could be employed in improving treatment strategies and in combinatorial drug therapy.

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“…Due to the homology of human Pgp and Pdr5p, the research on efflux pump modulators often exploits S. cerevisiae. It was shown that Pdr5p was inhibited by steroids such as progesterone, estradiol and deoxycorticosterone and some of their synthetic derivatives [111][112][113]. Inhibition of Pdr5p was also observed for some flavonoids like 6-(3,3-dimethylallyl)galangin, but the strongest effect was exhibited by phenothiazines [114,115].…”

Section: Modulation Of Multidrug Abc Transportersmentioning

confidence: 97%

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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Responses of Pathogenic and Nonpathogenic Yeast Species to Steroids Reveal the Functioning and Evolution of Multidrug Resistance Transcriptional Networks

Cited by 37 publications

References 41 publications

In VitroEffect of Malachite Green on Candida albicans Involves Multiple Pathways and Transcriptional RegulatorsUPC2andSTP2

In VitroEffect of Malachite Green on Candida albicans Involves Multiple Pathways and Transcriptional RegulatorsUPC2andSTP2

Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans

Yeast ABC proteins involved in multidrug resistance

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