Squalene epoxidase as the target of antifungal allylamines

The allylamine clinical antifungals naftifine and terbinafine inhibit ergosterol biosynthesis at the point of squalene epoxidation in a range of fungi pathogenic to man. Filamentous growth is particularly susceptible to this inhibition, cell death occurring at drug concentrations causing only partial inhibition of ergosterol biosynthesis. Susceptibility of yeast-like fungi such as Candida species is more variable. Squalene epoxidase, a membrane-bound enzyme, is the primary target of the allylamines. The C. albicans epoxidase is highly sensitive to the drugs and inhibition is unaffected by solubilisation of the enzyme. Squalene epoxidase from mammalian liver is orders of magnitude less sensitive to the allylamines. This selectivity appears to be partly due to interaction of the drugs with components of the soluble cytoplasm, but mostly due to intrinsic differences between the respective epoxidase enzymes.