Azole mechanism

Azoles are predominantly fungistatic. They inhibit C-14 α-demethylase (a cytochrome P450 [CYP450] enzyme), thereby blocking the demethylation of lanosterol to ergosterol, the principal sterol of fungal membranes This inhibition disrupts membrane structure and function, which, in turn, inhibits fungal cell growth [Note: Unfortunately, as is often the case for the initial member of a class of drugs, the selectivity of ketoconazole toward its target is not as precise as those of later azoles. For example, in addition to blocking fungal ergosterol synthesis, the drug also inhibits human gonadal and adrenal steroid synthesis, leading to decreased testosterone and cortisol production. In addition, ketoconazole inhibits CYP450-dependent hepatic drug-metabolizing enzymes.] With increasing use of azole antifungals, especially for long-term prophylaxis in immunocompromised and neutropenic patients, resistance is occurring, possibly via changes in the sensitivity of the target enzymes.