Mechanism of Action of Antifungal Drugs, with Special Reference to the Imidazole Derivatives

Abstract

Currently used antifungal drugs are distinct in terms of spectrum of activity, potency, therapeutic index, development of resistance, and mode of use. An important factor in the usefulnesss of a compound is the mechanism by which it attacks the structure and function of the fungal cell. The target organelles have been established for most antifungal drugs. Polyenes bind irreversibly to cell membranes. Alteration of the permeability of these structures precedes metabolic disruption and cell death. Griseofulvin deteriorates spindle and cytoplasmic microtubules, influencing cell division and outgrowth of hyphal tips. Flucytosine is deaminated to 5-fluorouracil, which is then phosphorylated and incorporated into RNA; protein synthesis is consequently impaired. A mechanism of action via inhibition of DNA synthesis is an alternative explanation. The imidazole derivatives inhibit the biosynthesis of ergosterol, the main sterol in membranes of fungi. These agents also affect the synthesis of triglycerides and phospholipids. Changes in oxidative and peroxidative enzyme activities, leading to an intracellular buildup of toxic concentrations of hydrogen peroxide, may contribute to the observed deterioration of subcellular organelles and to cell necrosis. The imidazole derivatives inhibit the transformation of blastospores of Candida albicans into the invasive mycelial form. This inhibition probably facilitates the task of host defense cells and may be the principal factor leading to clearance of infection.