Biochemical and morphological effects of polyamine biosynthesis inhibitors on Trichophyton and Microsporum

Abstract

The minimum inhibitory concentrations (MICs) of three known irreversible inhibitors of polyamine synthesis, alpha-difluoromethylornithine (DFMO) and monofluoromethyldehydroornithine methylester (MFMOme), inhibitors of ornithine decarboxylase (ODC) and alpha-difluoromethylarginine (DFMA), an inhibitor of arginine decarboxylase (ADC), were determined for 10 species of dermatophytic fungi. Trichophyton species were generally more sensitive to these inhibitors than Microsporum species. Both genera produced arginase, and treatment of members of either genus with DFMO or DFMA resulted in an inhibition of ODC activity and a depletion of cellular polyamines. However, conversion of labelled DFMA to DFMO, either in vivo or in vitro, could not be demonstrated in spite of both genera producing arginase. The ultrastructure of cells cultured in the presence of either DFMO or DFMA was similar, and revealed disruption of calcium metabolism, an increase in mitochondrial number and alterations to membrane systems. DFMA and DFMO also inhibited sporulation in Microsporum gypseum. Our findings indicate that DFMO limits the growth of dermatophytes by direct inhibition of ODC and lowering of cellular polyamine levels; in contrast, DFMA inhibits polyamine synthesis in an unspecified manner as ADC activity was undetected.