Bifonazole, a biochemist's view

Bifonazole, a new broad-spectrum antimycotic, interferes with sterol biosynthesis. Compared to clotrimazole, the primary mode of action of these two antimycotics is accepted to represent inhibition of the cytochrome P450-dependent hydroxylation at the sterol-C14-methyl group, which is the first step in C14-demethylation reaction. At least in dermatophytes bifonazole additionally inhibits directly HMG-CoA-reductase, the starting and regulatory Enzyme in terpenoid biosynthesis, whereas after application of clotrimazole the activity of HMG-CoA-reductase is only decreased by feed-back control, resulting from accumulation of dihydrolanosterol. The inhibition of HMG-CoA-reductase obviously is pathogen specific as the mammalian Enzyme is not affected. By this, in contrast to clotrimazole, bifonazole possesses a sequential mode of action, namely inhibition of cytochrome P450-dependent C14-demethylation of sterols and direct inhibition of HMG-CoA-reductase. In vitro bifonazole shows a strongly pH-dependent efficacy. The uptake kinetics of bifonazole have been measured with different pathogens. With respect to budding cells of Candida albicans it can be shown that the pH dependence of efficacy is due to a parallel pH dependence of the intracellular concentration of active ingredient. Even sublethal concentrations of bifonazole cause prior damages of young cells of C. albicans. These effects might explain the loss of infectivity of C. albicans after incubation with sublethal concentrations of bifonazole.