China
Africa
Explore chapters and articles related to this topic
Fungal Sterols
Published in Rajendra Prasad, Mahmoud A. Ghannoum, Lipids of Pathogenic Fungi, 2017
Yeast strains incapable of removing the 14-methyl group of lanosterol are quite easily isolated by selecting for resistance to azole antifungal agents. The sterol that accumulates, 14α-methyl fecosterol (Figure 3), is an “acceptable” sterol and is produced only if the mutant has a second deficiency in ergosterol biosynthesis.15 This deficiency is in the ERG3 structural gene, which has the information for 5,6-desaturase. Without erg3, erg11 mutants produce 14a-methyl-ergosta-8-ene-3,6-diol (Figure 4). This is apparently an unacceptable sterol in Saccharomyces, although a similar compound is produced in some mutants of Candida16-18 without any lethal effect. It seems reasonable to assume that C-5-desaturase is responsible for the formation of the diol. Whether the diol is a normal intermediate in the desaturation at C-5 has not been established. Mutants lacking 5,6-desaturase can grow on glucose with 14α-methyl fecosterol. Thus, the erg3 compensating mutant allows erg11 to grow aerobically. Under anaerobic conditions, where yeast can not synthesize sterols, the effect of the erg11 defect is not demonstrable. Those cells, like all yeast strains, must be provided with a suitable source of sterols to permit growth in the absence of oxygen. It is somewhat surprising that Candida can survive with the erg11 defect without compensating mutations while Saccharomyces can not. The variety of sterol mutants that have been reported in Saccharomyces is considerably greater than that in Candida. This suggests that Saccharomyces might be more tolerant of sterol alterations as compared to Candida. Alternatively, the Candida strains with the erg11 defect may have a silent suppressor (see below) that compensates for the aberrant sterols without affecting the production of that sterol.
In vitro and in vivo anti-Candida activity of citral in combination with fluconazole
Published in Journal of Oral Microbiology, 2022
Katherine Miranda-Cadena, Cristina Marcos-Arias, Aitzol Perez-Rodriguez, Iván Cabello-Beitia, Estibaliz Mateo, Elena Sevillano, Lucila Madariaga, Guillermo Quindós, Elena Eraso
With regard to the involvement of citral in the expression of the ERG11 gene, our findings were not conclusive. The relative changes in expression were not significant in any case, despite the fact that a slight ERG11 upregulation was observed. This could be due to the low concentrations of fluconazole used in this study [47]. However, in a previous study using carvacrol, down-regulated expression of ERG3 and ERG11 was described at different concentrations (IC, 25 mg/L, and 0.5× IC) [48]. Although ERG11 encodes an essential enzyme in the C. albicans pathway and the Hot-spot mutations and its overexpression are associated with fluconazole resistance, there are about 20 genes involved in the ergosterol biosynthesis, which have not been included in this study. Hence, if citral interferes with the ergosterol pathway, it should be independent to ERG11 or likely dose dependent, and other ERG genes should be considered. In addition, it is relevant to note that antifungal resistance is often the result of the sum of several mechanisms, and further study would be necessary for a better understanding.
Drug design strategies for the treatment azole-resistant candidiasis
Published in Expert Opinion on Drug Discovery, 2022
Setareh Moghimi, Mohammad Shafiei, Alireza Foroumadi
The third class of resistance has the most complicated mechanism, involving modulation of stress responses and changing the ergosterol biosynthesis pathway. Azoles, like other antifungals, interfere with cellular homeostasis and evolve significant and broad stress-response circuitry that enabled the fungal cell to grow and replicate. To date, some specific cellular signaling and many key signal transducers have been identified as responsible factors for the evolution and persistence of drug resistance in Candida species [31]. A key mechanism of stress responses by which C. albicans acquire azole resistance is through modulation of the ergosterol biosynthesis pathway. Many loss-of-function mutations in ERG3 led to the production of 14-α-methyl fecosterol instead of toxic methyl-sterols, allowing the cell to survive even in the presence of azoles [32].
Suppression of hyphal formation and virulence of Candida albicans by natural and synthetic compounds
Published in Biofouling, 2021
Fazlurrahman Khan, Nilushi Indika Bamunuarachchi, Nazia Tabassum, Du-Min Jo, Mohammad Mansoob Khan, Young-Mog Kim
Both fungal as well as human cells are eukaryotic. Hence, antifungal drugs are associated with a high risk of side effects (Revie et al. 2018). This has indeed become a major challenge in antifungal drug discovery (Y. Lee et al. 2021). Polyenes, azoles, and echinocandins constitute the three main groups of drugs for the treatment of fungal infections (Revie et al. 2018). These antifungal drugs act via different mechanisms of action. Polyeyenes (e.g. amphoteric B) function as a ‘sterol sponge’ by forming an extramembranous aggregate over the fungal cell membrane surface, and extracting ergosterol from it, a key component necessary for membrane integrity (Anderson et al. 2014). Azoles inhibit ergosterol synthesis by binding to the heme group in the active site of the cytochrome P450 enzyme (encoded by the Erg11 gene) (R. S. Shapiro et al. 2011; Revie et al. 2018). Furthermore, azoles have been shown to cause the accumulation of toxic sterol intermediates such as 14-α-methyl-3,6-diol, which is synthesized by the Erg3 gene (R. S. Shapiro et al. 2011). Echinocandins were shown to destroy the fungal cell walls composed of chitin, covalently connected 1,3-β-D-glucan and 1,6-β-D-glucan monomers, and mannan (Hasim and Coleman 2019). Antifungal echinocandins act by binding competitively to the catalytic subunit of 1,3-β-D-glucan synthase (encoded by Fks1), and thereby inhibiting this enzyme and destroying cell wall integrity, which ultimately leads to osmotic imbalance (Letscher-Bru and Herbrecht 2003; Perlin 2011).