Abstract
Candida species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans Candida species such as C. glabrata, C. parapsilosis, C. aureus, and C. krusei are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against Candida yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (C1) from barks of Drimys winteri and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (C2, C3, C4, and C5) was elucidated by 1D and 2D NMR spectroscopy resulting in C4 being a novel compound. Antifungal activity assays against C. albicans, C. glabrata, and C. krusei revealed that C4 exhibited an increased activity (IC50 of 75 μg/mL) compared to C1 (IC50 of 125 μg/mL) in all yeast strains. The antifungal activity of C1 and C4 was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that C1 and C4 bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol (LAN) to the catalytic pocket. Binding free energy estimates suggested that C4 forms a more stable complex with the enzyme than C1, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of Candida species as inhibitors of 14-alpha demethylase.
Highlights
Candidiasis is a common opportunistic yeast infection caused by Candida species that affects more than 250,000 people and causes more than 50,000 deaths every year [1]
Candidiasis is the infection caused by the yeast Candida, among them Candida albicans is the most prevalent species
Resistance in C. glabrata is more common in North America but was not detected in Asia-Pacific and Latin America, and C. parapsilosis with resistance to fluconazole was noted in Europe, but it was not detected in Asia-Pacific or Latin America, while Candida krusei resistance to azole have been observed only in North America [38]
Summary
Candidiasis is a common opportunistic yeast infection caused by Candida species that affects more than 250,000 people and causes more than 50,000 deaths every year [1]. Fluconazole is the most widely prescribed antifungal agent This compound inhibits the enzyme lanosterol-C14α-demethylase (CYP51) responsible for ergosterol biosynthesis by lanosterol demethylation [4]. Several non-albicans Candida species show resistance to antifungal drugs, for instance Candida krusei is intrinsically resistant to antifungals, whereas Candida glabrata acquires resistance after exposure to antifungal agents by the overexpression of multidrug transporters [5,6]. These undesired effects highlight the relevance of discovering novel antifungal agents against yeast infections caused by Candida species
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