Primary Site of Action of Ketoconazole on Candida Albicans

Ketoconazole, an antifungal drug, completely inhibited the growth of Candida albicans 7N at concentrations of greater than or equal to 50 microgram/ml (94 microM). However, ketoconazole incompletely inhibited the growth of this opportunistic yeast at concentrations of 25 to 0.2 microgram/ml (47 to 0.4 microM). At these lower concentrations, 2,3,5-triphenyl tetrazolium chloride, an electron acceptor, was reduced by several strains of C. albicans. This effect resulted in red coloration of colonies. Concomitantly, this phenomenon was not antagonized in the presence of ergosterol. Furthermore, neither ketoconazole nor antimycin A inhibited the growth of C. albicans under anaerobic conditions, as revealed by a paper disk method. Ketoconazole at the concentrations stated above inhibited endogenous and exogenous respiration immediately after it was added to a system containing log phase C. albicans cells, as determined polarographically. At the same time, ketoconazole inhibited the activity of NADH oxidase at the mitochondrial level. In contrast, higher concentrations of ketoconazole (greater than 100 microM) were required to inhibit the activity of succinate oxidase from rat liver mitochondria. In addition, concentrations of ketoconazole greater than 100 microM were required to impair the uptake of labeled leucine and adenine and, subsequently, the incorporation of the former into protein and the latter into DNA and RNA in intact cells. On the other hand, ketoconazole at concentrations of 10, 1.0, and 0.4 microM had no effect on either membrane permeability or macromolecular synthesis.