Abstract
To explore action mechanism of butenafine hydrochloride (butenafine), a novel antifungal agent, the biochemical effect of the drug on a susceptible dimorphic fungus Sporothrix schenchii in the yeast-phase of growth was studied. The results are summarized as follows :
(1) As monitored by viable counts of fungal cultures, 1.1× 10-7 M and higher concentrations of butenafine almost completely inhibited growth, with time-dependent decrease of viable counts starting after 24 hours of exposure.
(2) Butenafine at concentrations of 5×10-8 M or above markedly inhibited biosynthesis of ergosterol and induced intracellular accumulation of large amounts of squalene.
(3) Substantial amounts of K+ and inorganic phosphate were rapidly released from the fungal cells after exposure to 1.4×10-4 M or higher concentrations of butenafine. The rate and extent, of release of these cellular components increased with increasing drug concentrations in the medium and time of exposure. Consistent with this, corresponding concentrations of butenafine also caused a rapid increase in the pH value of the cell suspension.
(4) All the experimental results lead us to the postulations that butenafine has a dual mechanisms of antifungal action. First, like existing allylamines and thiocarbamates, it would primarily inhibit squalene epoxidation and resultant inhibition of biosynthesis of ergosterol could attribute to the antifungal activity of the drug. The second action mechanism of butenafine by which it inhibits fungal growth would be a direct damaging effect on the cell membrane, although this effect was demonstrated at higher drug concentrations. It would be also suggested that, in highly susceptible fungi such as S. schenchii, the former action mechanism plays a major role in the antifungal activity of butenafine, while in less susceptible fungi the latter one does so.
