Glutathione Utilization by Candida albicans Requires a Functional Glutathione Degradation (DUG) Pathway and OPT7, an Unusual Member of the Oligopeptide Transporter Family

Desai, Prashant R.; Thakur, Anil; Ganguli, Dwaipayan; Paul, Sanjoy; Morschhäuser, Joachim; Bachhawat, Anand K.

doi:10.1074/jbc.m111.272377

Cited by 18 publications

(13 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S. cerevisiae lacking c-glutamyl cysteine synthase (Gsh1), the first enzyme in glutathione biosynthesis, leads to glutathione autotrophy in which the cells dependent on exogenous GSH for its growth and survival [63,64]. In the absence of endogenous GSH, yeast has the ability to uptake GSH from an environment through high-affinity glutathione transporters such as Hgt1 [63–65]. In the present study, we also demonstrated that gsh1Δ and gsh2Δ homozygous deletion strains has relatively low amount of basal GSH when compared to wild type and the counterpart heterozygous deletion strains.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of low amount of GSH in these deletion strains was further depleted by ebselen treatment and in turn places cells in oxidative stress. Importance and essentiality of GSH has also been demonstrated in other fungi species including Candida [60,65], suggesting that glutathione might form an attractive novel target for the development of new antifungal drugs [66–68]. Future studies are required to delineate the interaction between ebselen and yeast GSH, and also the affinity of ebselen towards mammalian GSH.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

Thangamani

Eldesouky

Mohammad

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

View full text Add to dashboard Cite

Background Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remains unclear. Methods The antifungal effect of ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of ebselen. Ebselen’s antifungal activity in vivo was investigated in a Caenorhabditis elegans animal model. Results Ebselen exhibits potent antifungal activity against both Candida spp. and Cryptococcus spp, at concentrations ranging from 0.5 – 2 μg/ml. Ebselen rapidly eradicates a high fungal inoculum within two hours of treatment. Investigation of the drug’s antifungal mechanism of action indicates that ebselen depletes intracellular glutathione (GSH) levels, leading to increased production of reactive oxygen species (ROS), and thereby disturbs the redox homeostasis in fungal cells. Examination of ebselen’s in vivo antifungal activity in two Caenorhabditis elegans models of infection demonstrate that ebselen is superior to conventional antifungal drugs (fluconazole, flucytosine and amphotericin) in reducing Candida and Cryptococcus fungal load. Conclusion Ebselen possesses potent antifungal activity against clinically relevant isolates of both Candida and Cryptococcus by regulating GSH and ROS production. The potent in vivo antifungal activity of ebselen supports further investigation for repurposing it for use as an antifungal agent. General significance The present study shows that ebselen targets glutathione and also support that glutathione as a potential target for antifungal drug development.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

Thangamani

Eldesouky

Mohammad

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

View full text Add to dashboard Cite

show abstract

“…However, our knowledge on the role of sulphur metabolism for fungal virulence has remained scarce. Only two studies have specifically addressed the importance of the sulphur-containing molecule glutathione in C. albicans and C. glabrata to demonstrate that glutathione biosynthesis, but not its uptake or degradation, is essential for virulence [23]. Accordingly, glutathione appears not to be the sulphur source these Candida species exploit in vivo , and its relevance for pathogenesis is probably due to its impact on iron metabolism [72].…”

Section: Discussionmentioning

confidence: 99%

“…Only a few studies have addressed its relevance for fungal virulence so far, focusing on synthesis and utilization of the sulphur-containing molecule glutathione in Candida albicans or C. glabrata [23], [24]. The importance of sulphur metabolism for aspergillosis has not been addressed to date.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Sulphur Assimilation Is Essential for Virulence and Affects Iron Homeostasis of the Human-Pathogenic Mould Aspergillus fumigatus

et al. 2013

View full text Add to dashboard Cite

Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

show abstract

“…These studies demonstrated that at least OPT1 to OPT5 encode functional peptide transporters, while Opt6 to Opt8 might have a more specific, narrower substrate spectrum that is not sufficient to allow growth on peptides generated by SAP-mediated digestion of BSA (6). Indeed, OPT7 has recently been found to encode a glutathione transporter (17).…”

mentioning

confidence: 99%

Roles of Different Peptide Transporters in Nutrient Acquisition in Candida albicans

et al. 2013

Self Cite

View full text Add to dashboard Cite

Fungi possess two distinct proton-coupled peptide transport systems, the dipeptide/tripeptide transporters (PTR) and the oligopeptide transporters (OPT), which enable them to utilize peptides as nutrients. In the pathogenic yeast Candida albicans, peptide transporters are encoded by gene families consisting of two PTR genes and eight OPT genes. To gain insight into the functions and importance of specific peptide transporters, we generated mutants lacking the two dipeptide/tripeptide transporters Ptr2 and Ptr22, as well as the five major oligopeptide transporters Opt1 to Opt5. These mutants were unable to grow in media containing peptides as the sole nitrogen source. Forced expression of individual peptide transporters in the septuple mutants showed that Ptr2 and Ptr22 could utilize all tested dipeptides as substrates but differed in their abilities to transport specific tripeptides. Interestingly, several oligopeptide transporters, which are thought to transport peptides consisting of more than three amino acids, also mediated the uptake of tripeptides. Opt1 especially turned out to be a highly flexible transporter that enabled growth on all tripeptides tested and could even utilize a dipeptide, a function that has never been ascribed to this family of peptide transporters. Despite their inability to grow on proteins or peptides, the opt1⌬ opt2⌬ opt3⌬ opt4⌬ opt5⌬ ptr2⌬ ptr22⌬ septuple mutants had no in vivo fitness defect in a mouse model of gastrointestinal colonization. Therefore, the nutritional versatility of C. albicans enables it to utilize alternative nitrogen sources in this host niche, which probably contributes to its success as a commensal and pathogen in mammalian hosts.

show abstract

Glutathione Utilization by Candida albicans Requires a Functional Glutathione Degradation (DUG) Pathway and OPT7, an Unusual Member of the Oligopeptide Transporter Family

Cited by 18 publications

References 34 publications

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

Regulation of Sulphur Assimilation Is Essential for Virulence and Affects Iron Homeostasis of the Human-Pathogenic Mould Aspergillus fumigatus

Roles of Different Peptide Transporters in Nutrient Acquisition in Candida albicans

Contact Info

Product

Resources

About