Action of imidazole-containing antifungal drugs

During the past few years several promising new antifungal drugs (e.g. miconazole and ketoconazole) have emerged from a large and diverse group of synthetic imidazole-containing compounds. Potentially, these agents could provide the first major break-through in the management of systematic mycoses in over 20 years. Although this review briefly traces the historical development of antifungal imidazoles and summarizes pertinent information regarding chemical characteristics, biological properties, and growth inhibitory activities, it is primarily concerned with experimental findings and current ideas with respect to mode of action. Physiological, biochemical, and cytological studies have established that the primary adverse effect of imidazoles on fungal cells is disorganization of the plasma membrane. Normal structural and permeability characteristics of the membrane are altered to the extent that the fungal cell cannot adequately govern cytoplasmic levels of essential ions and low molecular weight metabolites. This much seems clear, but the biochemical mechanisms involved in membrane disorganization have not been resolved. There are currently two major hypotheses, each of which is based on substantial experimental evidence. The first suggests that imidazoles interfere with one or more enzymatic steps in the biosynthesis of ergosterol, an integral sterol component of fungal cell membranes. In the second hypothesis, membrane disorganization is explained in purely physicochemical terms. It is postulated that imidazoles and unsaturated fatty acid components of the membrane undergo hydrophobic interactions that are the direct cause of structural alterations and loss of normal permeability controls.