Biochemical Targets for Antifungal Azole Derivatives: Hypothesis on the Mode of Action

Overview of medically important antifungal azole derivatives

“…At present, the specific ways in which the antifungal imidazoles and triazoles affect fungal cells have not been characterized. There is a growing body of evidence that the primary mode of action of these antifungal drugs is the inhibition of ergosterol biosynthesis in the cytoplasmic membrane of fungi, resulting in the accumulation of lanosterol or other sterol intermediates (25,290,325). Vanden Bossche and co-workers (325)(326)(327) and other investigators (186,270) have demonstrated with a number of antifungal azole derivatives that these compounds affect cytochrome P-450 involved in the 14a-demethylation of lanosterol.…”

“…There is a growing body of evidence that the primary mode of action of these antifungal drugs is the inhibition of ergosterol biosynthesis in the cytoplasmic membrane of fungi, resulting in the accumulation of lanosterol or other sterol intermediates (25,290,325). Vanden Bossche and co-workers (325)(326)(327) and other investigators (186,270) have demonstrated with a number of antifungal azole derivatives that these compounds affect cytochrome P-450 involved in the 14a-demethylation of lanosterol. Fluconazole and itraconazole are more selective for the fungal cytochrome P-450 isozymes than is ketoconazole; thus, mammalian physiology is less seriously disturbed by the newer triazoles as compared to the imidazole ketoconazole.…”

Compounds active against cell walls of medically important fungi

“…This phenomenon is probably a result of the previously described secondary effects of azoles on chitin synthesis (107,188,255) being compounded by the specific inhibition of this polymer by nikkomycin. The usefulness of this approach has yet to be determined because the effect is limited to certain ratios of the two compounds, making dosing problematic.…”

“…This has been shown to be true for other membrane-active antibiotics as well. Studies of the effects of azoles on chitin synthesis in vivo in C. albicans have demonstrated that within certain ranges of concentrations a net stimulation of chitin synthesis can ensue (107,187,255). In the case of the azoles, the depletion of ergosterol in the cytoplasmic membranes of treated cells likely results in a secondary effect on the activity of the membrane-bound chitin synthetase, perhaps by activation of the zymogenic form of this enzyme (255).…”

“…The aforementioned compounds share a target in that they all interfere with the structural integrity of the fungal cytoplasmic membrane: amphotericin B by physical disruption of the membrane, and azoles by blocking synthesis of the ergosterol component (1,44,255). Even the allylamines, a new class of agent recently introduced to the market, share this target by interfering with squalene epoxidase activity (204).…”