Abstract
The minimum growth-inhibitory concentrations (MIC) of clotrimazole, a synthetic antifungal agent, the chemical and common names of which are 2, 4-bisphenyl-[2-chlorophenyl]-1-imidazolyl methane and BAY b 5097, respectively, ranged from 0.5 to 4μg/ml against clinical isolates of Candida albicans. This agent proved to be fungistatic at about MIC (2μg/ml) and fungicidal at higher concentrations (above 20μg/ml) to growing cultures of the Candida albicans 6713 strain as a main test organism.
Cultures treated with the drug were osmotically stable. The drug had no effect on the endogenous respiratory activity of intact C. albicans cells or the oxidation, as well as the coupled phosphorylation, by isolated mitochondria thereof with exogenous NADH and succinate as substrates. It caused a marked decrease in cellular dry weight in short periods following the addition at fungicidal concentrations.
Studies with radioactive precursors revealed that a marginal fungicidal concentration of clotrimazole inhibited syntheses of protein, RNA, DNA, lipid, and wall polysaccharides by intact cells, particularly protein and RNA. Even with higher levels of the drug, however, its effect on endogenous or poly U-directed polypeptide synthesis from cell-free extracts was consistently negative.
Cells treated with the drug showed a conspicuous decrease in RNA content, but the addition of the drug to crude cell-free extracts did not cause RNA breakdown. The minimum fungicidal concentration of the drug caused a marked enhancement of leakage of intracellular phosphorous compounds into the ambient medium with concomitant breakdown of cellular nucleic acids. Acceleration of K+- efflux in treated cells also occurred to the corresponding extent.
From these results it is presumed that clotrimazole may primarily display its action by damaging the permeability barrier, possibly through the reaction with the cell membrane, of sensitive organisms.
