Spermidine-analogous triamines suppressed the growth of Candida albicans

We examined the antifungal activity of various synthetic triamines on several fungi. Among various triamines having a general structure H2N(CH2)aNH(CH2)bNH2 (a=2-5, b=3-8), some triamines (a=4 or 5) showed inhibitory effect on the growth of Candida albicans and C. tropicalis. Determination of the minimum inhibitory concentrations (MICs) of these triamines on C. albicans showed that triamine 4-8 (a=4, b=8) and triamine 5-8 had strong antifungal activity. Further analysis revealed that the antifungal effect of triamine 4-8 was fungistatic and the antifungal effect was diminished by the addition of spermidine, a physiological triamine, to the medium. These results suggested that triamine 4-8 is antagonistic to spermidine and the antifungal activity is due to the suppression of the action of intrinsic polyamines. On the agar medium, C. albicans formed microcolonies even in the presence of triamine 4-8 by long cultivation. We then observed the form of C. albicans using microscope and found that the cells cultivated with triamine 4-8 were round, similar to the yeast form, while most of the cells on the agar medium without triamine 4-8 were hyphal form. Subsequently, we investigated the synergistic effect of two compounds with triamine 4-8, cyclohexylamine and dl-α-difluoromethylornithine which are inhibitors of enzymes involving in the biosynthesis of physiological polyamines such as spermidine. The results showed that the antifungal activity of triamine 4-8 increased by the addition of these enzyme inhibitors.