Mechanism of Action of Efinaconazole, a Novel Triazole Antifungal Agent

Abstract

The mechanism of action of efinaconazole, a new triazole antifungal, was investigated with Trichophyton mentagrophytes and Candida albicans. Efinaconazole dose-dependently decreased ergosterol production and accumulated 4,4-dimethylsterols and 4␣-methylsterols at concentrations below its MICs. Efinaconazole induced morphological and ultrastructural changes in T. mentagrophytes hyphae that became more prominent with increasing drug concentrations. In conclusion, the primary mechanism of action of efinaconazole is blockage of ergosterol biosynthesis, presumably through sterol 14␣-demethylase inhibition, leading to secondary degenerative changes. Ergosterol is an important structural component of fungal cell membranes, maintaining membrane fluidity and a permeability barrier, and is essential for fungal cell viability (1-3). Several classes of antifungal drugs target ergosterol biosynthesis. Among these, triazole antifungals (e.g., itraconazole) and imidazole antifungals (e.g., clotrimazole and miconazole) inhibit sterol 14␣-demethylase (14-DM) in the ergosterol biosynthesis pathway (4). The consequent ergosterol depletion affects cell membrane integrity and function and is believed to inhibit fungal cell growth and affect morphology.Efinaconazole, a novel triazole antifungal drug currently under development as a topical treatment for onychomycosis, has demonstrated efficacy in patients with toenail onychomycosis in two phase 3 clinical trials (5). Onychomycosis and other superficial mycoses are caused mainly by dermatophytes (e.g., Trichophyton rubrum and Trichophyton mentagrophytes) and yeast (e.g., Candida albicans). Efinaconazole possesses similar or higher antifungal activity against T. rubrum and T. mentagrophytes (MIC range, 0.00098 to 0.031 g/ml) and a broader spectrum of activity than those of currently marketed antifungals used in onychomycosis (6). We investigated the effects of efinaconazole on fungal ergosterol biosynthesis and dermatophyte hyphal morphology.In the present study, T. mentagrophytes strain SM-110 and C. albicans strain ATCC 10231 were used. The MICs of efinaconazole (Kaken Pharmaceutical), itraconazole, and clotrimazole (SigmaAldrich) were determined by the broth microdilution method using morpholinepropanesulfonic acid (MOPS)-buffered RPMI 1640, as described in CLSI documents M38-A2 (7) and M27-A3 (8), using visual endpoint readings of 80% growth inhibition at 4 days and 50% growth inhibition at 48 h, respectively. Efinaconazole was 4-fold more active than itraconazole against T. mentagrophytes SM-110 (MICs of 0.0039 and 0.016 g/ml, respectively). Similarly, efinaconazole was 8-fold more active than clotrimazole against C. albicans ATCC 10231 (MICs of 0.00098 and 0.0078 g/ml, respectively). The two strains showed typical susceptibilities to the antifungals tested, consistent with previous findings for these species (6, 9).Ergosterol biosynthesis assays were conducted by modifying the methods of Vanden Bossche et al. (10) and Ryder et al. (11). T. mentagrophytes (2 ϫ 10 8 microconidia/ml...

Inhibitory effect of nerol against Aspergillus niger on grapes through a membrane lesion mechanism

“…Some recognized antifungal drugs, including triazole and azole compounds, inhibit cell growth through sterol 14-demethylase (14-DM) in the ergosterol biosynthesis pathway (Sheehan, Hitchcock, & Sibley, 1999). Ergosterol depletion and 14-methylsterol accumulation resulting from 14-DM inhibition interfere with functions of ergosterol in fungal cell membranes, resulting in changes to membrane fluidity and activities of several membrane-bound enzymes (e.g., chitin synthase), which may induce cell membrane damage and morphological changes (Maertens, 2004;Tatsumi et al, 2013). In our experiment, the sterol quantitation method is an absolute measurement and indicative of the ergosterol and 24(28)dehydroergosterol contents based on the exclusive spectral absorption pattern produced between 230 and 300 nm by extracted sterols.…”

Pathogenesis of microbial keratitis

“…The azoles including imidazoles and triazoles, at low concentrations inhibit ergosterol biosynthesis while, cause direct damage to cell walls at higher concentrations [188]. Fluconazole and ketoconazole show good intraocular penetration and are therefore good agents against keratitis with deep lesions [137].…”

Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy

“…In regard to the influence of these antifungal agents on the morphology of the hyphal cells of T. mentagrophytes, as analyzed by electron microscopy, only a few cases have been reported (12)(13)(14)(15)(16)(17). SEM and/or TEM analysis of all drugs studied, mostly ergosterol synthesis inhibitors, revealed common cellular changes, including the thickening of the hyphal cell wall and accumulation of electron-dense granules in the cell wall (12)(13)(14)(15)(16)(17). The reported granular structures are speculated to be agglomerates of intermediates of sterol metabolism that accumulated during the process of ergosterol synthesis inhibition (18,19).…”