Abstract
The resistance of Candida albicans to azole drugs represents a great global challenge. This study investigates the potential fungicidal effects of atorvastatin (ATO) combinations with fluconazole (FLU), itraconazole (ITR), ketoconazole (KET) and voriconazole (VOR) against thirty-four multidrug-resistant (MDR) C. albicans using checkerboard and time-kill methods. Results showed that 94.12% of these isolates were MDR to ≥ two azole drugs, whereas 5.88% of them were susceptible to azole drugs. The tested isolates exhibited high resistance rates to FLU (58.82%), ITR (52.94%), VOR (47.06%) and KET (35.29%), whereas only three representative (8.82%) isolates were resistant to all tested azoles. Remarkably, the inhibition zones of these isolates were increased at least twofold with the presence of ATO, which interacted in a synergistic (FIC index ≤ 0.5) manner with tested azoles. In silico docking study of ATO and the four azole drugs were performed against the Lanosterol 14-alpha demethylase enzyme (ERG11) of C. albicans. Results showed that the mechanism of action of ATO against C. albicans is similar to that of azole compounds, with a docking score (−4.901) lower than azole drugs (≥5.0) due to the formation a single H-bond with Asp 225 and a pi–pi interaction with Thr 229. Importantly, ATO combinations with ITR, VOR and KET achieved fungicidal effects (≥ 3 Log10 cfu/ml reduction) against the representative isolates, whereas a fungistatic effect (≤ 3 Log10 cfu/ml reduction) was observed with FLU combination. Thus, the combination of ATO with azole drugs could be promising options for treating C. albicans infection.
Highlights
Fungal diseases kill more than 1.5 million per year and affect over a billion people
The susceptibility of thirty-four C. albicans isolates to five different antifungal agents was evaluated through the determination of the MIC using the broth microdilution method
Another study conducted in Egypt reported that 100% of C. albicans isolates were resistant to FLU and VOR (El-Houssaini et al 2019)
Summary
Fungal diseases kill more than 1.5 million per year and affect over a billion people. They are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable (Bongomin et al 2017). Candida genus is one the most important opportunistic fungi responsible for high morbidity and mortality worldwide, especially with immunocompromised hosts. The members of this genus can cause vaginitis, oral candidiasis, cutaneous. The limited number of antifungal drugs represents a leading cause of morbidity and mortality of fungal infections worldwide. The toxicity of current antifungal drugs and the increasing incidence of Candida infections, associated with the emergence of pathogens that are highly resistant to most antifungal agents, as well as the emergence of drug-resistance by nonalbicans strains of Candida, have demanded steady research and development of new antifungal drugs that exert their effects by alternative mechanisms of action and combined
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