Design and synthesis of potential inhibitors of the ergosterol biosynthesis as antifungal agents

Chung, Sung‐Kee; Lee, Ki-Wha; Kang, Heui Il; Yamashita, Chika; Kudo, Makiko; Yoshida, Yuzo

doi:10.1016/s0968-0896(00)00177-2

Cited by 18 publications

(13 citation statements)

References 26 publications

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“…Indeed, this has already been confirmed with some transition-state analogues, and dual inhibitors of CYP51 and ERG6 have also been reported [60].…”

Section: Erg6 (Sterol C-24 Methyltransferases)supporting

confidence: 59%

“…Therefore, several transition-state analogue inhibitors of ERG6 with nM K i values have already been designed [58]. As fungal cells treated with antifungal azoles often respond with mutations, and alternated pathway of ergosterol synthesis [58], dual inhibitors might be more efficient than inhibitors of the individual enzymes [60].…”

Section: Potential Application Of Ergosterol Biosynthetic Enzymesmentioning

confidence: 99%

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Steroid-transforming enzymes in fungi

Kristan¹,

Rižner²

2012

The Journal of Steroid Biochemistry and Molecular Biology

129

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“…Indeed, this has already been confirmed with some transition-state analogues, and dual inhibitors of CYP51 and ERG6 have also been reported [60].…”

Section: Erg6 (Sterol C-24 Methyltransferases)supporting

confidence: 59%

Section: Potential Application Of Ergosterol Biosynthetic Enzymesmentioning

confidence: 99%

Steroid-transforming enzymes in fungi

Kristan¹,

Rižner²

2012

The Journal of Steroid Biochemistry and Molecular Biology

129

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“…Though some promising compounds with in vitro activities against Erg6p have already been synthesised (e.g. [ 53 – 54 ]), much more work is still needed to develop new and efficient antifungal drugs targeting ergosterol biosynthesis, mainly due to a rapidly increasing number of clinical isolates resistant to classical ergosterol-pathway-targeted antifungal drugs [ 55 – 56 ].…”

Section: Resultsmentioning

confidence: 99%

Changes in the Sterol Composition of the Plasma Membrane Affect Membrane Potential, Salt Tolerance and the Activity of Multidrug Resistance Pumps in Saccharomyces cerevisiae

Kodedová¹,

Sychrová²

2015

PLoS ONE

140

114

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We investigated the impact of the deletions of genes from the final steps in the biosynthesis of ergosterol (ERG6, ERG2, ERG3, ERG5, ERG4) on the physiological function of the Saccharomyces cerevisiae plasma membrane by a combination of biological tests and the diS-C3(3) fluorescence assay. Most of the erg mutants were more sensitive than the wild type to salt stress or cationic drugs, their susceptibilities were proportional to the hyperpolarization of their plasma membranes. The different sterol composition of the plasma membrane played an important role in the short-term and long-term processes that accompanied the exposure of erg strains to a hyperosmotic stress (effect on cell size, pH homeostasis and survival of yeasts), as well as in the resistance of cells to antifungal drugs. The pleiotropic drug-sensitive phenotypes of erg strains were, to a large extent, a result of the reduced efficiency of the Pdr5 efflux pump, which was shown to be more sensitive to the sterol content of the plasma membrane than Snq2p. In summary, the erg4Δ and erg6Δ mutants exhibited the most compromised phenotypes. As Erg6p is not involved in the cholesterol biosynthetic pathway, it may become a target for a new generation of antifungal drugs.

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“…We found several interesting patterns after transfer to nitrogen-deficient (Y-D) medium that may be associated with stationary phase such as histone H1, important for DNA packaging [93]. Erg6 is a protein in the ergosterol biosynthetic pathway, used as a lipid droplet marker, and a target of antifungals [94, 95]. It has also been identified by proteomics in Y. lipolytica lipid droplets [56], and here shows changing lipid droplet size and number.…”

Section: Resultsmentioning

confidence: 99%

A molecular genetic toolbox for Yarrowia lipolytica

Bredeweg

Pomraning

Dai

et al. 2017

Biotechnol Biofuels

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Background Yarrowia lipolytica is an ascomycete yeast used in biotechnological research for its abilities to secrete high concentrations of proteins and accumulate lipids. Genetic tools have been made in a variety of backgrounds with varying similarity to a comprehensively sequenced strain.ResultsWe have developed a set of genetic and molecular tools in order to expand capabilities of Y. lipolytica for both biological research and industrial bioengineering applications. In this work, we generated a set of isogenic auxotrophic strains with decreased non-homologous end joining for targeted DNA incorporation. Genome sequencing, assembly, and annotation of this genetic background uncovers previously unidentified genes in Y. lipolytica. To complement these strains, we constructed plasmids with Y. lipolytica-optimized superfolder GFP for targeted overexpression and fluorescent tagging. We used these tools to build the “Yarrowia lipolytica Cell Atlas,” a collection of strains with endogenous fluorescently tagged organelles in the same genetic background, in order to define organelle morphology in live cells.ConclusionsThese molecular and isogenetic tools are useful for live assessment of organelle-specific protein expression, and for localization of lipid biosynthetic enzymes or other proteins in Y. lipolytica. This work provides the Yarrowia community with tools for cell biology and metabolism research in Y. lipolytica for further development of biofuels and natural products.Electronic supplementary materialThe online version of this article (doi:10.1186/s13068-016-0687-7) contains supplementary material, which is available to authorized users.

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Design and synthesis of potential inhibitors of the ergosterol biosynthesis as antifungal agents

Cited by 18 publications

References 26 publications

Steroid-transforming enzymes in fungi

Steroid-transforming enzymes in fungi

Changes in the Sterol Composition of the Plasma Membrane Affect Membrane Potential, Salt Tolerance and the Activity of Multidrug Resistance Pumps in Saccharomyces cerevisiae

A molecular genetic toolbox for Yarrowia lipolytica

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