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

Elias, Daniel; Hervay, Nora Tóth; Bujdoš, Marek; Gbelská, Yvetta

doi:10.3390/jof9050579

Cited by 6 publications

(3 citation statements)

References 61 publications

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“…Moreover, the in vivo evolved strains 15 and 17 that carry ERG6 mutations are the only Clade III variants anticipated to endure treatment as per model projection (Figure 5), supporting the strength of our model predictions. In two recent studies, ERG6 was found to be essential in iron homeostasis, oxidative and membrane stress tolerance in C. glabrata 68,69 , which might explain the lower SR for H2O2, SDS and EDTA of the sterol alteration type 4 strains observed (Figure 4). Interestingly, a general increased (relative to wt) resistance to cell wall stressors (CFW and CR) accompanies the LoF of ERG6 (Fugure 4), which suggests a role of ERG6 in cell wall integrity as shown in C. glabrata 69 .…”

Section: Discussionmentioning

confidence: 85%

Acquired amphotericin B resistance and fitness trade-off compensation in Candida auris

Carolus,

Sofras,

Boccarella

et al. 2023

Preprint

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Candida auris is an emergent human fungal pathogen of growing concern due to common drug resistance to all major antifungal drug classes. Although resistance to amphotericin B (AMB) has been detected in 30 to 60% of clinical isolates of C. auris, mechanisms of AMB resistance remain poorly characterized. Here we present a large-scale investigation of how AMB resistance can be acquired through genetic adaptation. We typed 441 in vitro and in vivo evolved C. auris lineages from four AMB-susceptible clinical strains of different clades. We show a great diversity of acquired resistance responses with resistance magnitude- and strain-dependent fitness trade-offs. Genotyping and membrane sterol analyses of selected lineages show four major types of membrane sterol alterations. Using a novel, plasmid-based CRISPR-Cas9 allele editing method and Cas9-RNP meditated gene deletions, we show that AMB resistance can be acquired through variation in several sterol biosynthesis regulators including ERG6, NCP1, ERG11, ERG3, HMG1, ERG10 and ERG12. Additionally, we show how aneuploidies in chromosomes 4 and 6 emerge during AMB resistance evolution. By leveraging fitness trade-off phenotyping and mathematical modelling of the in vivo environment during treatment, we evaluated the potential of different mechanisms to establish resistant infections and discover a mechanism of fitness trade-off compensation. Variation in CDC25 substantially enhanced the capacity to establish a resistant infection and may have played a role in facilitating the sole documented clinical case of acquired AMB resistance during treatment in C. auris. In summary, our findings show that fitness trade-off compensation along with several sterol modulating mechanisms of acquired AMB resistance represent a potential risk for AMB treatment failure in the clinic.

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Section: Discussionmentioning

confidence: 85%

Acquired amphotericin B resistance and fitness trade-off compensation in Candida auris

Carolus,

Sofras,

Boccarella

et al. 2023

Preprint

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“…One explanation for the lack of increased triazole susceptibility upon erg6 repression in A. fumigatus may be that loss of Erg6 activity induces resistance to oxidative stress thereby abrogating this secondary mechanism. We do not believe this to be involved as previous work has shown that loss of erg6 actually increases susceptibility to oxidative stress in C. glabrata 58 , and repression of erg6 expression does not result in resistance to the oxidative damage-inducing compound, menadione (Fig. S 7F ).…”

Section: Discussionmentioning

confidence: 99%

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Xie,

Rybak,

Martin-Vicente

et al. 2024

Nat Commun

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Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.

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“…When the flux of the ergosterol synthesis pathway decreases, intracellular iron accumulates improperly, which trigger ROS accuculation in cells through the Fenton or Haber-Weiss reactions. Toxic to cells, excess iron replaces copper and zinc in metalloproteins, thereby altering their enzymatic activity ( Elias et al, 2023 ). In summary, the accumulation of ROS in the strain ERG6 Δ under non-CA stress may be caused by excessive accumulation of iron.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide identification of resistance genes and response mechanism analysis of key gene knockout strain to catechol in Saccharomyces cerevisiae

Liao,

Li,

Chen

et al. 2024

Front. Microbiol.

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Engineering Saccharomyces cerevisiae for biodegradation and transformation of industrial toxic substances such as catechol (CA) has received widespread attention, but the low tolerance of S. cerevisiae to CA has limited its development. The exploration and modification of genes or pathways related to CA tolerance in S. cerevisiae is an effective way to further improve the utilization efficiency of CA. This study identified 36 genes associated with CA tolerance in S. cerevisiae through genome-wide identification and bioinformatics analysis and the ERG6 knockout strain (ERG6Δ) is the most sensitive to CA. Based on the omics analysis of ERG6Δ under CA stress, it was found that ERG6 knockout affects pathways such as intrinsic component of membrane and pentose phosphate pathway. In addition, the study revealed that 29 genes related to the cell wall-membrane system were up-regulated by more than twice, NADPH and NADP+ were increased by 2.48 and 4.41 times respectively, and spermidine and spermine were increased by 2.85 and 2.14 times, respectively, in ERG6Δ. Overall, the response of cell wall-membrane system, the accumulation of spermidine and NADPH, as well as the increased levels of metabolites in pentose phosphate pathway are important findings in improving the CA resistance. This study provides a theoretical basis for improving the tolerance of strains to CA and reducing the damage caused by CA to the ecological environment and human health.

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

Cited by 6 publications

References 61 publications

Acquired amphotericin B resistance and fitness trade-off compensation in Candida auris

Acquired amphotericin B resistance and fitness trade-off compensation in Candida auris

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Genome-wide identification of resistance genes and response mechanism analysis of key gene knockout strain to catechol in Saccharomyces cerevisiae

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