Abstract
In order to characterize the mechanism of antifungal action of a new imidazole antimycotic, SS717, the effects of this drug on growth, viability, ergosterol biosynthesis, cell membrane permeability, and several other metabolic parameters were studied using a wild-type strain of Candida albicans (TIMM 0144) and two mutant strains therefrom which were resistant to vibunazole and had a reduced ability to synthesize ergosterol.
SS717 exhibited a similarly potent fungicidal activity at a concentration of 80μg/ml or above toward both the wild-type strain and the two mutant strains. Whereas IC99 values of SS717 for the two mutant strains increased only 7 to 8 fold, their IC50 values increased 82 to 129 fold over corresponding values of the wild-type strain. Biosynthesis of total lipids and alkali-insoluble glucan of the wild-type strain was inhibited by this drug to a greater extent than that of other macromolecules at concentrations below 40μg/ml. However, ergosterol biosynthesis was much more sensitive to SS717, which caused a potent inhibition even at concentrations as low as 0.08μg/ml. Apart from this effect, SS717 at concentrations above 20μg/ml induced a rapid release of intracellular K+ and PO43- from the wild-type strain, as well as a rapid elevation of pH of an ambient medium, probably the result of K+ release. The extent of K+ release induced at drug concentrations above 20μg/ml from cells of the mutant strains was equal to or greater than that from the wild-type strain cells.
On the basis of all these results, it is suggested that SS717 at relatively low concentrations exerts fungistatic action mainly through inhibition of ergosterol biosynthesis, while at higher concentrations the drug achieves fungicidal action mainly by directly damaging the cell membrane. It is further likely that a change of the lipid composition of the cell membrane produced by the former action secondarily amplifies the latter action.
