Investigation of an S-Adenosylmethionine:Δ24-Sterol Methyltransferase in Ergosterol Biosynthesis in Yeast

The developing resistance in fungi has become a key challenge, which is being faced nowadays with the available antifungal agents in the market. Further search for novel compounds from different sources has been explored to meet this problem. The current review describes and highlights recent advancement in the antifungal drug aspects from plant and marine based sources. The current available antifungal agents act on specific targets on the fungal cell wall, like ergosterol synthesis, chitin biosynthesis, sphingolipid synthesis, glucan synthesis etc. We discuss some of the important anti-fungal agents like azole, polyene and allylamine classes that inhibit the ergosterol biosynthesis. Echinocandins inhibit β-1, 3 glucan synthesis in the fungal cell wall. The antifungals poloxins and nikkomycins inhibit fungal cell wall component chitin. Apart from these classes of drugs, several combinatorial therapies have been carried out to treat diseases due to fungal resistance. Recently, many antifungal agents derived from plant and marine sources showed potent activity. The renewed interest in plant and marine derived compounds for the fungal diseases created a new way to treat these resistant strains which are evident from the numerous literature publications in the recent years. Moreover, the compounds derived from both plant and marine sources showed promising results against fungal diseases. Altogether, this review article discusses the current antifungal agents and highlights the plant and marine based compounds as a potential promising antifungal agents.

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Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

Medicinal Chemistry ◽

10.2174/1573406415666181203115957 ◽

2019 ◽

Vol 15 (6) ◽

pp. 648-658 ◽

Cited By ~ 1

Author(s):

Manzoor Ahmad Malik ◽

Shabir Ahmad Lone ◽

Parveez Gull ◽

Ovas Ahmad Dar ◽

Mohmmad Younus Wani ◽

...

Keyword(s):

Schiff Base ◽

Candida Albicans ◽

Antifungal Activity ◽

Fungal Infections ◽

Total Sterol ◽

Antifungal Drugs ◽

New Drugs ◽

Ergosterol Biosynthesis ◽

Dependent Manner ◽

Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

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The Negative Effect of Protein Phosphatase Z1 Deletion on the Oxidative Stress Tolerance of Candida albicans Is Synergistic with Betamethasone Exposure

Journal of Fungi ◽

10.3390/jof7070540 ◽

2021 ◽

Vol 7 (7) ◽

pp. 540

Author(s):

Ágnes Jakab ◽

Tamás Emri ◽

Kinga Csillag ◽

Anita Szabó ◽

Fruzsina Nagy ◽

...

Keyword(s):

Oxidative Stress ◽

Candida Albicans ◽

Protein Phosphatase ◽

Combined Treatment ◽

Specific Protein ◽

Ergosterol Biosynthesis ◽

Acid Oxidation ◽

Menadione Sodium Bisulfite ◽

Rnaseq Data ◽

Negative Effect

The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial Candida infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus specific protein phosphatase Z1 (CaPpz1) has a pivotal role in oxidative stress response of Candida albicans and was proposed as a potential antifungal drug target. The aim of this study was to investigate the combined effects of CaPPZ1 gene deletion and MSB treatment in BM pre-treated C. albicans cultures. We found that the combined treatment increased redox imbalance, enhanced the specific activities of antioxidant enzymes, and reduced the growth in cappz1 mutant (KO) strain. RNASeq data demonstrated that the presence of BM markedly elevated the number of differentially expressed genes in the MSB treated KO cultures. Accumulation of reactive oxygen species, increased iron content and fatty acid oxidation, as well as the inhibiting ergosterol biosynthesis and RNA metabolic processes explain, at least in part, the fungistatic effect caused by the combined stress exposure. We suggest that the synergism between MSB treatment and CaPpz1 inhibition could be considered in developing of a novel combinatorial antifungal strategy accompanying steroid therapy.

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Plant‐derived tabersonine exert its antifungal activity by repressing the expression of ergosterol biosynthesis and cell wall mannoprotein encoding genes in Saccharomyces cerevisiae

Letters in Applied Microbiology ◽

10.1111/lam.13446 ◽

2020 ◽

Author(s):

Wenhui Ma ◽

Yu Zhao ◽

Yanyan Wang

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Wall ◽

Antifungal Activity ◽

Ergosterol Biosynthesis ◽

Encoding Genes

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Camphor and Eucalyptol—Anticandidal Spectrum, Antivirulence Effect, Efflux Pumps Interference and Cytotoxicity

International Journal of Molecular Sciences ◽

10.3390/ijms22020483 ◽

2021 ◽

Vol 22 (2) ◽

pp. 483

Author(s):

Marija Ivanov ◽

Abhilash Kannan ◽

Dejan S. Stojković ◽

Jasmina Glamočlija ◽

Ricardo C. Calhelha ◽

...

Keyword(s):

Fungal Pathogens ◽

Efflux Pump ◽

Efflux Pumps ◽

Liver Cells ◽

Ergosterol Biosynthesis ◽

Antifungal Compound ◽

Porcine Liver ◽

Fungal Virulence ◽

Genes Encoding ◽

Plant Constituents

Candidaalbicans represents one of the most common fungal pathogens. Due to its increasing incidence and the poor efficacy of available antifungals, finding novel antifungal molecules is of great importance. Camphor and eucalyptol are bioactive terpenoid plant constituents and their antifungal properties have been explored previously. In this study, we examined their ability to inhibit the growth of different Candida species in suspension and biofilm, to block hyphal transition along with their impact on genes encoding for efflux pumps (CDR1 and CDR2), ergosterol biosynthesis (ERG11), and cytotoxicity to primary liver cells. Camphor showed excellent antifungal activity with a minimal inhibitory concentration of 0.125–0.35 mg/mL while eucalyptol was active in the range of 2–23 mg/mL. The results showed camphor’s potential to reduce fungal virulence traits, that is, biofilm establishment and hyphae formation. On the other hand, camphor and eucalyptol treatments upregulated CDR1;CDR2 was positively regulated after eucalyptol application while camphor downregulated it. Neither had an impact on ERG11 expression. The beneficial antifungal activities of camphor were achieved with an amount that was non-toxic to porcine liver cells, making it a promising antifungal compound for future development. The antifungal concentration of eucalyptol caused cytotoxic effects and increased expression of efflux pump genes, which suggests that it is an unsuitable antifungal candidate.

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