Azoles

Pharmaceutical effect on Membrance Permeability

The antifungal azoles prevent the synthesis of ergosterol in the fungal membrane. These compounds block ergosterol synthesis by interfering with the demethylation of its precursor, lanosterol. Lanosterol demethylase is a cytochrome P450 enzyme and, although azole antifungals have much less influence on analogous mammalian systems, some of the side effects of these drugs are attributable to such action. Antifungal azole derivatives are predominantly fungistatic but some compounds at higher concentrations, notably miconazole and clotrimazole, kill fungi apparently by causing direct membrane damage. Other, less well characterized, effects of azoles on fungal respiration have also been described.

Pharmaceutical Applications

A large group of synthetic agents, which includes drugs used in bacterial and parasitic infections (5-nitroimidazoles; benzimidazoles). Antifungal azoles have in common an imidazole or triazole ring with N-carbon substitution. The activity is essentially fungistatic, but some of the newer triazoles exert fungicidal effects at therapeutic concentrations. They are effective in the topical treatment of dermatophytoses and superficial forms of candidosis; several are suitable for systemic administration.
Several molecular mechanisms of resistance have been elucidated. These include overexpression of efflux pump genes, point mutations in the gene that encodes the target enzyme, lanosterol demethylase, and overexpression of this gene. Changes in other enzymes involved in ergosterol biosynthesis, such as sterol desaturase, may also contribute to azole resistance.