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Lipids and Dimorphism of Candida Albicans and Sporothrix Schenckii
Published in Rajendra Prasad, Mahmoud A. Ghannoum, Lipids of Pathogenic Fungi, 2017
The major sterol in C. albicans is ergosterol both in the yeast and mycelial forms and the minor components include 4-methylenezymosterol, 4,14-dimethylzymosterol and 24-methylene-dihydrolanosterol14,15 (Table 3). In a study on the plasma membrane sterols,16 the yeast cell membrane has been shown to contain 50% ergosterol and 12% calciferol of total free sterols, while the mycelial cell membrane contains 42% ergosterol and 16% zymosterol. It should be, however, noted that the major esterified sterol is zymosterol with only small amount of esterified ergosterol. The esterified zymosterol is possibly transported to the cell wall.16 However, esterified sterols could be contaminants of stored lipids, because they are thought to be a storage form of sterols in the cytosolic inclusions.11 On the other hand, Ghannoum et al. showed by gas chromatography and mass spectrometry that cholesterol is also present in lipid fraction extracted from mycelial cells by Folch’s method, but not in the yeast form of C. albicans10231.6 They suggested that most of cholesterol exists as cholesteryl mannoside, whose biological function(s) is unknown.
Design, synthesis and in vitro biological studies of novel triazoles with potent and broad-spectrum antifungal activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Junhe Bao, Yumeng Hao, Tingjunhong Ni, Ruina Wang, Jiacun Liu, Xiaochen Chi, Ting Wang, Shichong Yu, Yongsheng Jin, Lan Yan, Xiaomei Li, Dazhi Zhang, Fei Xie
Gas chromatography-mass spectrometry (GC-MS) was used to examine the composition of sterols in fungal cells as a preliminary method to verify whether our target compounds inhibit Cyp5115. Therefore, compounds A1, A3, A9 and FCZ at 8 µg/mL were used to treat C. albicans SC5314, and their sterol profiles were analysed as shown in Figure 4. As the major fungal sterol, ergosterol accounted for 89.85% of the total sterols in the control group, zymosterol accounted for 8.80%, in addition to several other sterols. When treated with either FCZ, A1, A3, or A9 the ergosterol content of the fungal cells decreased to 6.08%, 5.44%, 5.63% and 5.17%, respectively. In contrast, the content of other sterols in the bypass pathway increased. For instance, treatment with A1 resulted in the following: the proportion of lanosterol, 14α-methylfecosterol, eburicol and obtusifoliol increased to 23.42%, 31.11%, 19.29% and 20.09%, respectively. Our target compounds had a consistent effect and the same mechanism of action as FCZ by inhibiting the production of ergosterol on Cyp51.
Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Fabrice Pagniez, Nicolas Lebouvier, Young Min Na, Isabelle Ourliac-Garnier, Carine Picot, Marc Le Borgne, Patrice Le Pape
GC-MS analysis of sterol profile of three different clinical strains of C. albicans (CAAL93), C. krusei (CAKR7) and C. glabrata (CAGL2) showed ergosterol as the major sterol accounting for 69% to 83% of total cellular sterols. Small quantities of ergosterol intermediates such as zymosterol, ergosta-7,22-dienol, fecosterol and episterol were also detected to a lesser extent (between 2% and 5%). Ergosterol precursor in Candida, i.e. lanosterol, was also found in a small quantity (0.7% to 5.2%). These sterol profiles were in accordance with classical metabolism of ergosterol27. Treatment with 8 g (4 ng/mL) of C. albicans fluconazole-susceptible strain (CAAL93 – MIC = 0.125 µg/mL) resulted in a significant reduction of ergosterol content (70%), an accumulation of lanosterol and the emerging of 14α-methyl sterols such as eburicol, 14α-methylfecosterol and 14α-methylepisterol. Same modifications in sterol profile were observed when CAAL93 was treated with fluconazole at a 1000-fold higher dose (4 µg/mL) (Table 3).
Advances in preclinical approaches to Chagas disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Fernando Villalta, Girish Rachakonda
The sterol14α-demethylase is by far the enzyme of the ergosterol pathway that has been studied in more detail as a therapeutic target for T. cruzi. This enzyme uses lanosterol or related compounds as substrates to produce zymosterol, which is the precursor of ergosterol. Azoles are highly effective antifungal drugs that work by inhibiting the activity of sterol 14α-demethylases. Several novel azoles have shown strong anti-T. cruzi activity in vitro and in vivo [20,21,29], so they have been considered a priority for drug development. The mechanism of action of these compounds against the T. cruzi 14α-demethylase has been studied at the structural level [29–32].