A Small Molecule Inhibitor of Erg251 Makes Fluconazole Fungicidal by Inhibiting the Synthesis of the 14α-Methylsterols

Lu, Hui; Li, Wanqian; Whiteway, Malcolm; Wang, Hongkang; Zhu, Shuo; Ji, Zhe; Feng, Yanru; Yan, Lan; Fang, Ting; Li, Liping; Ni, Tingjunhong; Zhang, Xiaolong; Lv, Quan-Zhen; Ding, Zichao; Qiu, Lijuan; Zhang, Dazhi; Jiang, Yuanying

doi:10.1128/mbio.02639-22

Cited by 19 publications

(35 citation statements)

References 68 publications

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“…fold increased expression in erg251∆/∆ in the presence of FLC relative to ERG251/ERG251 (Fig 6C), and over-expression of ERG6 can result in accumulation of the alternative sterols leading to cell survival in the presence of FLC[21,27,69]. This is consistent with a recent report showing that with FLC exposure, erg251∆/∆ has a depletion of ergosterol and an accumulation of the sterol precursors for the toxic dienol(Lu et al 2023). These results support the homozygous deletion of ERG251 can lead to upregulation of alternative sterols that promote survival in presence of FLC.…”

supporting

confidence: 90%

“…In contrast, genes that are involved in oxidative stress response like SOD5 and AOX2 were up-regulated (Fig 3A and 3B) [57,58]. These changes in lipid metabolism and stress response may affect metabolism and nutrient availability more broadly including carbon and amino acid metabolism [20,59].…”

Section: Resultsmentioning

confidence: 99%

“…Both the late and alternate pathways of ergosterol biosynthesis utilize C-4 sterol methyl oxidase, the catalytic component of the C-4 demethylation complex that is responsible for removing the two methyl groups from the C-4 position of the sterol molecule [20,21,38]. In Saccharomyces cerevisiae, Erg25 is the solo C-4 sterol methyl oxidase and essential for standard growth [21,39].…”

Section: Introductionmentioning

confidence: 99%

“…In Saccharomyces cerevisiae, Erg25 is the solo C-4 sterol methyl oxidase and essential for standard growth [21,39]. However, both Aspergillus fumigatus and C. albicans encode two membrane C-4 sterol methyl oxidases with one of them serving as the primary enzyme during biosynthesis [19,20,38]. In C. albicans , ERG251 encodes the primary C-4 sterol methyl oxidase, but few studies have characterized it independently and the findings are contradictory.…”

Section: Introductionmentioning

confidence: 99%

“…In C. albicans , ERG251 encodes the primary C-4 sterol methyl oxidase, but few studies have characterized it independently and the findings are contradictory. For example, erg251Δ/Δ exhibited increased fluconazole (FLC) susceptibility and accumulation of eburicol, the direct precursor for 14α-methylfecosterol, in the presence of FLC [20]. However, in a haploid C. albicans strain, transposon insertion into ERG251 resulted in decreased FLC susceptibility [36].…”

Section: Introductionmentioning

confidence: 99%

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Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

Zhou,

Hilk,

Solis

et al. 2024

Preprint

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Ergosterol is essential for fungal cell membrane integrity and growth, and numerous antifungal drugs target ergosterol. Inactivation or modification of ergosterol biosynthetic genes can lead to changes in antifungal drug susceptibility, filamentation and stress response. Here, we found that the ergosterol biosynthesis gene ERG251 is a hotspot for point mutations during adaptation to antifungal drug stress within two distinct genetic backgrounds of Candida albicans. Heterozygous point mutations led to single allele dysfunction of ERG251 and resulted in azole tolerance in both genetic backgrounds. This is the first known example of point mutations causing azole tolerance in C. albicans. Importantly, single allele dysfunction of ERG251 in combination with recurrent chromosome aneuploidies resulted in bona fide azole resistance. Homozygous deletions of ERG251 caused increased fitness in low concentrations of fluconazole and decreased fitness in rich medium, especially at low initial cell density. Dysfunction of ERG251 resulted in transcriptional upregulation of the alternate sterol biosynthesis pathway and ZRT2, a Zinc transporter. Notably, we determined that overexpression of ZRT2 is sufficient to increase azole tolerance in C. albicans. Our combined transcriptional and phenotypic analyses revealed the pleiotropic effects of ERG251 on stress responses including cell wall, osmotic and oxidative stress. Interestingly, while loss of either allele of ERG251 resulted in similar antifungal drug responses, we observed functional divergence in filamentation regulation between the two alleles of ERG251 (ERG251-A and ERG251-B) with ERG251-A exhibiting a dominant role in the SC5314 genetic background. Finally, in a murine model of systemic infection, homozygous deletion of ERG251 resulted in decreased virulence while the heterozygous deletion mutants maintain their pathogenicity. Overall, this study provides extensive genetic, transcriptional and phenotypic analysis for the effects of ERG251 on drug susceptibility, fitness, filamentation and stress responses.

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supporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

Zhou,

Hilk,

Solis

et al. 2024

Preprint

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Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans

Zhen,

Wang,

Feng

et al. 2024

Advanced Science

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Candidiasis, which presents a substantial risk to human well‐being, is frequently treated with azoles. However, drug‐drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)‐approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle‐mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole‐mediated liver enzyme inhibition and avoids export‐mediated drug resistance in C. albicans.

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Geldanamycin confers fungicidal properties to azole by triggering the activation of succinate dehydrogenase

Xiong,

Wang,

Feng

et al. 2024

Life Sciences

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A Small Molecule Inhibitor of Erg251 Makes Fluconazole Fungicidal by Inhibiting the Synthesis of the 14α-Methylsterols

Cited by 19 publications

References 68 publications

Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans

Geldanamycin confers fungicidal properties to azole by triggering the activation of succinate dehydrogenase

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