Erg6p is essential for antifungal drug resistance, plasma membrane properties and cell wall integrity in <i>Candida glabrata</i>

Elias, Daniel; Hervay, Nora Tóth; Jacko, Juraj; Morvová, Marcela; Valachovič, Martin; Gbelská, Yvetta

doi:10.1093/femsyr/foac045

Cited by 11 publications

(17 citation statements)

References 49 publications

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“…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 . A recent study shows that three AMB resistant clinical isolates show hyper resistance towards cell wall perturbating agents such as CFW, CR and caffeine, compared to an AMB susceptible strain 24 .…”

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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“…Increased susceptibility has been reported for erg6 null mutants of S. cerevisiae , K. lactis and C. neoformans 14 , 17 , whereas a C. albicans Δerg6 mutant maintains wild-type susceptibility profiles 16 . C. glabrata and C. auris clinical isolates with erg6 mutation displays increased susceptibility to triazoles 37 , 50 , but C. glabrata null mutants generated in laboratory strains revealed increased tolerance 15 . Additionally, reduced resistance to triazoles has been reported in several erg null mutants along with ergosterol reduction or depletion 53 – 55 .…”

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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“…Notably, in our study we found that Erg6A is essential for the viability of A. fumigatus. In contrast, Erg6A homologes of yeasts are not essential for viability 22,30,31 . Consequently, the sterol C24-methyltransferase could represent a specific antifungal target in fungi that have an ergosterol biosynthesis pathway similar to that of A. fumigatus, similar as it was proposed recently 32 .…”

Section: Discussionmentioning

confidence: 96%

Toxic eburicol accumulation drives the antifungal activity of azoles againstAspergillus fumigatus

Elsaman,

Golubtsov,

Brazil

et al. 2024

Preprint

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Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11), a key enzyme in the ergosterol biosynthesis pathway. They have fungistatic effects against yeasts but fungicidal effects against molds. The molecular basis for this difference remained unknown. The sequence of enzymatic steps required for ergosterol biosynthesis is different in yeasts and molds. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic moldAspergillus fumigatusstrictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not result in comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3β,6α-diol, the “toxic diol” responsible for the antifungal effects of azoles in yeasts, is not required for the fungicidal effects inA. fumigatus. In contrast to yeast, where a lack of ERG3 functionality causes azole resistance,A. fumigatuslacking ERG3 becomes more azole susceptible. Mutants lacking mitochondrial complex III functionality, which are less susceptible to the fungicidal effects of azoles, but get strongly inhibited in growth, convert eburicol much more efficiently into the supposedly “toxic diol”. Our results support a mechanistic model where the mode of action of azoles against the pathogenic moldA. fumigatus, other than in yeast, relies on the accumulation of eburicol which exerts fungicidal effects by triggering the formation of cell wall carbohydrate patches.

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Erg6p is essential for antifungal drug resistance, plasma membrane properties and cell wall integrity in Candida glabrata

Cited by 11 publications

References 49 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

Toxic eburicol accumulation drives the antifungal activity of azoles againstAspergillus fumigatus

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