Mathematical Modeling of Fluconazole Resistance in the Ergosterol Pathway of Candida albicans

Abstract

Candidiasis is reported as 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, most common species of which is the Candida albicans. The ergosterol pathway in yeast is a common target by many antifungal agents since 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 calls for a need to 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: (1) a partial inhibition of the sterol-methyltransferase enzyme yields a fair amount of fluconazole resistance, (2) an overexpression of the ERG6 gene, leading to increased sterol-methyltransferase enzyme, is a good target of antifungals as an adjunct to fluconazole, (3) a partial inhibition of lanosterol yields a fair amount of fluconazole resistance, (4) the C5-desaturase enzyme is not a good target of antifungals as an adjunct to fluconazole, (5) the C14-demethylase enzyme is confirmed to be a good target of fluconazole, and (6) the dose-dependent effect of fluconazole is confirmed. This study hopes to aid experimenters narrow down the possible drug targets prior to doing costly and time-consuming experiments, and to serve as a cross-validation tool for experimental data.