The Absence of PDR16 Gene Restricts the Overexpression of CaSNQ2 Gene in the Presence of Fluconazole in Candida albicans

Bencova, Alexandra; Goffa, Eduard; Morvová, Marcela; Valachovič, Martin; Griač, Peter; Hervay, Nora Tóth; Gbelská, Yvetta

doi:10.1007/s11046-020-00459-4

Cited by 9 publications

(4 citation statements)

References 52 publications

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“…Despite the large number of transporters found in the C. albicans genome, evidence of transporter overexpression in resistant clinical isolates is currently limited to ABC-Ts CDR1 and CDR2 and MFS-Ts MDR1 and PDR16 (Figure 3) [1,111,131,133]. CDR1 and CDR2 overexpression is frequently observed in clinical isolates, and coregulation of these two pumps is evident [36].…”

Section: Drug Efflux Pump/transporter Genes and Resistant Mutationsmentioning

confidence: 99%

“…Efflux pump overexpression can be further induced by upstream GOF mutations, regulating transcription factor genes (Table 3) [59,[125][126][127][128][129][130]144,145]. In C. albicans, the CDR1, CDR2 and PDR16 transporters, as well as MDR1, are regulated by zinc-cluster (Zn2-Cys6) transcription factors Tac1 and Mrr1, respectively [111,121,131,133,144,146]. Other potential transcriptional regulators of CDR1 expression include Tup1 (thymidine uptake 1) and Ncb2 (β subunit of the NC2 complex) [147].…”

Section: Transcriptional Regulators Of Transporter Genesmentioning

confidence: 99%

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Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species

Czajka,

Venkataraman,

Brabant-Kirwan

et al. 2023

Cells

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Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic Candida species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in Candida species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: tac1 and mrr1; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent Candida species. Notably, N. glabrata, P. kudriavzevii and C. auris demonstrate fluconazole resistance.

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Section: Drug Efflux Pump/transporter Genes and Resistant Mutationsmentioning

confidence: 99%

Section: Transcriptional Regulators Of Transporter Genesmentioning

confidence: 99%

Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species

Czajka,

Venkataraman,

Brabant-Kirwan

et al. 2023

Cells

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“…The susceptibility of the parental strain to various cytotoxic compounds was compared with that of the Cgerg6∆ deletion mutant. Susceptibility was determined using spot assay [41]. To assess C. glabrata susceptibility to various oxidative stress inducing agents, we plated the cells on the solid growth media containing different concentrations of hydrogen peroxide, menadione and diamide.…”

Section: Susceptibility Assaysmentioning

confidence: 99%

Essential Role of CgErg6p in Maintaining Oxidative Stress Tolerance and Iron Homeostasis in Candida glabrata

Elias

Hervay

Bujdoš

et al. 2023

JoF

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The human pathogenic fungus Candida glabrata is the second leading cause of candidemia, a life-threatening invasive mycosis. Clinical outcomes are complicated by reduced susceptibility of C. glabrata to azoles together with its ability to evolve stable resistance to both azoles and echinocandins following drug exposure. Compared to other Candida spp., C. glabrata displays robust oxidative stress resistance. In this study, we investigated the impact of CgERG6 gene deletion on the oxidative stress response in C. glabrata. CgERG6 gene encodes sterol-24-C-methyltransferase, which is involved in the final steps of ergosterol biosynthesis. Our previous results showed that the Cgerg6Δ mutant has a lower ergosterol content in its membranes. Here, we show that the Cgerg6Δ mutant displays increased susceptibility to oxidative stress inducing agents, such as menadione, hydrogen peroxide and diamide, accompanied with increased intracellular ROS production. The Cgerg6Δ mutant is not able to tolerate higher concentrations of iron in the growth media. We observed increased expression of transcription factors, CgYap1p, CgMsn4p and CgYap5p, together with increased expression of catalase encoding the CgCTA1 gene and vacuolar iron transporter CgCCC1 in the Cgerg6Δ mutant cells. However, it seems that the CgERG6 gene deletion does not influence the function of mitochondria.

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“…The most distinct phenotype observed due to the absence of Pdr16p is an increased sensitivity to inhibitors of the post-lanosterol step of the sterol biosynthetic pathway, azole antifungals and amorolfine [11,17,18]. Importantly, the increased sensitivity of pdr16D cells to commonly used azole-based antifungal drugs was observed not only in S. cerevisiae but also in the pathogenic yeasts Candida albicans [19,20], Candida glabrata [21], and Cryptococcus neoformans [22]. It is, thus, of immense importance to understand in molecular detail the mechanism by which Pdr16p performs its role in yeast and fungal cells.…”

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confidence: 99%

Yeast Sec14‐like lipid transfer proteins Pdr16 and Pdr17 bind and transfer the ergosterol precursor lanosterol in addition to phosphatidylinositol

et al. 2022

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Yeast Sec14-like phosphatidylinositol transfer proteins (PITPs) contain a hydrophobic cavity capable of accepting a single molecule of phosphatidylinositol (PI) or another molecule in a mutually exclusive manner. We report here that two yeast Sec14 family PITPs, Pdr16p (Sfh3p) and Pdr17p (Sfh4p), possess high-affinity binding and transfer towards lanosterol. To our knowledge, this is the first identification of lanosterol transfer proteins. In addition, a pdr16Dpdr17D double mutant had a significantly increased level of cellular lanosterol compared with the corresponding wild-type. Based on the lipid profiles of wild-type and pdr16Dpdr17D cells grown in aerobic and anaerobic conditions, we suggest that PI-lanosterol transfer proteins are important predominantly for the optimal functioning of the post-lanosterol part of sterol biosynthesis.

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The Absence of PDR16 Gene Restricts the Overexpression of CaSNQ2 Gene in the Presence of Fluconazole in Candida albicans

Cited by 9 publications

References 52 publications

Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species

Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species

Essential Role of CgErg6p in Maintaining Oxidative Stress Tolerance and Iron Homeostasis in Candida glabrata

Yeast Sec14‐like lipid transfer proteins Pdr16 and Pdr17 bind and transfer the ergosterol precursor lanosterol in addition to phosphatidylinositol

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