Mode of action of miconazole on yeasts: inhibition of the mitochondrial ATPase

Miconazole [( 1-[2-(2,4 dichlorophenyl)-2-(2,4 dichlorophenyl)methoxy]ethyl]-1 H-imidazole) completely inhibited growth of Saccharomyces cerevisiae and Candida albicans on glycerol at 10 microM . 50 microM was needed to achieve the same effect during growth on glucose. Miconazole inhibited competitively the mitochondrial ATPase of S. cerevisiae with a Ki of 1 microM. F1 activity of the enzyme was not affected. Mutants resistant to miconazole were isolated. The ATPase of these mutants was resistant to 10 microM miconazole. Higher concentrations of miconazole inhibited the ATPase of the plasma membrane. The inhibition of the S. cerevisiae enzyme was competitive with a Ki of 50 microM. The results point to the mitochondrial ATPase as the primary target of miconazole action at least during growth on non-fermentable carbon sources.