Ketoconazole is an antifungal imidazole, known as the brand name Extina, Ketodan, Ketoderm, Nizoral, Xolegel. It is typically applied as a topical cream since there are now better oral anti-fungal drugs with less side-effects. Ketoconazole is used for treatment or prevention of fungal infections including blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. It is most commonly used for athlete's foot, jock itch, ringworm, and certain kinds of dandruff. It is recommended that oral Ketoconazole be used only when other anti-fungal drugs are not an option. It is also used to treat Cushing's syndrome. It does this by targetting Steroid 17-alpha-hydroxylase/17,20 lyase which is essential in cortisol synthesis. This is only approved for in Europe. Ketoconazole works like other antifungal azoles by inhibiting lanosterol 14-alpha demethylase which is an enzyme that catalyzes the synthesis of 4,4-Dimethylcholesta-8,14,24-trienol from Lanosterol. This is one of the first steps in Ergosterol synthesis. The inhibition of lanosterol 14-alpha demethylase prevents the synthesis of ergosterol which is essential in the maintenance and synthesis of fungal cell membranes. The lack of ergosterol increases cell permeability which allows intracellular components to leak out and eventually the fungal cell collapses and dies. Fungal cells also require ergosterol to synthesize new cell membranes for buds and new cells, and so they cannot do so when the synthesis of ergosterol is inhibited. Ketoconazole also causes an accumulation of 14α-methyl-3,6-diol which is toxic to the cell and will also kill the fungal cell and the cell membrane. The exact method of 14α-methyl-3,6-diol synthesis is not known, but it has been found in a study that lanosterol is catalyzed by Methylsterol monooxygenase and 3-keto-steroid reductase along with ERG26 to synthesize 14α-methyl-fecosterol. This only occurs when lanosterol 14-alpha demethylase is inhibited. 14α-methyl-fecosterol is catalyzed by Delta(7)-sterol 5(6)-desaturase to synthesize 14α-methyl-3,6-diol.

Ketoconazole Anti-fungal Pathway References