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Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in Candida albicans Causing Ergosterol Biosynthesis Inhibition

ABSTRACT: Candida albicans is the most dominant and prevalent cause of fungal infections in humans. Azoles are considered as first-line drugs for the treatment of these infections. However, their prolonged and insistent use has led to multidrug resistance and treatment failures. To overcome this, modification or derivatization of the azole ring has led to the development of new and effective antifungal molecules. In a previous study, we reported on the development of new triazole-based molecules as potential antifungal agents against Candida auris. In this study, the most potent molecules from the previous study were docked and simulated with lanosterol 14-alpha demethylase enzyme. These compounds were further evaluated for in vitro susceptibility testing against C. albicans. In silico results revealed favorable structural dynamics of the compounds, implying that the compounds would be able to effectively bind to the target enzyme, which was further manifested by the strong interaction of the test compounds with the amino acid residues of the target enzyme. In vitro studies targeting quantification of ergosterol content revealed that pta1 was the most active compound and inhibited ergosterol production by >90% in both drug-susceptible and resistant C. albicans isolates. Furthermore, RT-qPCR results revealed downregulation of ERG11 gene when C. albicans cells were treated with the test compound, which aligns with the decreased ergosterol content. In addition, the active triazole derivatives were also found to be potent inhibitors of biofilm formation. Both in silico and in vitro results indicate that these triazole derivatives have the potential to be taken to the next level of antifungal drug development.

SUBMITTER: Rather I

PROVIDER: S-EPMC9323696 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Candidiasis is reported to be the most common fungal infection in the critical care setting. The causative agent of this infection is a commensal pathogen belonging to the genus Candida, the most common species of which is Candida albicans. The ergosterol pathway in yeast is a common target by many antifungal agents, as ergosterol is an essential component of the cell membrane. The current antifungal agent of choice for the treatment of candidiasis is fluconazole, which is classified under the azole antifungals. In recent years, the significant increase of fluconazole-resistant C. albicans in clinical samples has revealed the need for a search for other possible drug targets. In this study, we constructed a mathematical model of the ergosterol pathway of C. albicans using ordinary differential equations with mass action kinetics. From the model simulations, we found the following results: (i) a partial inhibition of the sterol-methyltransferase enzyme yields a fair amount of fluconazole resistance; (ii) the overexpression of the ERG6 gene, which leads to an increased sterol-methyltransferase enzyme, is a good target of antifungals as an adjunct to fluconazole; (iii) a partial inhibition of lanosterol yields a fair amount of fluconazole resistance; (iv) the C5-desaturase enzyme is not a good target of antifungals as an adjunct to fluconazole; (v) the C14α-demethylase enzyme is confirmed to be a good target of fluconazole; and (vi) the dose-dependent effect of fluconazole is confirmed. This study hopes to aid experimenters in narrowing down possible drug targets prior to costly and time-consuming experiments and serve as a cross-validation tool for experimental data. IMPORTANCE Candidiasis is reported to be the most common fungal infection in the critical care setting, and it is caused by a commensal pathogen belonging to the genus Candida, the most common species of which is Candida albicans. The current antifungal agent of choice for the treatment of candidiasis is fluconazole, which is classified under the azole antifungals. There has been a significant increase in fluconazole-resistant C. albicans in recent years, which has revealed the need for a search for other possible drug targets. We constructed a mathematical model of the ergosterol pathway in C. albicans using ordinary differential equations with mass action kinetics. In our simulations, we found that by increasing the amount of the sterol-methyltransferase enzyme, C. albicans becomes more susceptible to fluconazole. This study hopes to aid experimenters in narrowing down the possible drug targets prior to costly and time-consuming experiments and to serve as a cross-validation tool for experimental data.

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Triazole Derivatives Target 14α–Demethylase (LDM) Enzyme in Candida albicans Causing Ergosterol Biosynthesis Inhibition

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