Inhibitory effect of a new mycotic agent, piritetrate on ergosterol biosynthesis in pathogenic fungi.
A new antimycotic agent piritetrate, a thiocarbamate derivative, was found to interfere with fungal sterol biosynthesis. Sterol biosynthesis was measured by means of incorporation of radioactivity from [14C]acetate into individual sterol fractions and their precursor compounds extracted from cells of Candida albicans, Cryptococcus neoformans, and Trichophyton mentagrophytes. Piritetrate was a much more potent inhibitor of fungal squalene epoxidation than a related drug, naphthiomate. The greater antifungal efficacy of the former was reflected in its greater inhibitory action on sterol biosynthesis than the latter. Such inhibitory effects were also demonstrated in in vitro labelling experiments with [14C]mevalonate on the S10 fraction (10,000 g supernatant of homogenate) of C. albicans cells. At 5 x 10(-7) M concentration, piritetrate gave almost 90% inhibition of ergosterol biosynthesis in the S10 fraction of C. albicans cells. Furthermore, this agent was highly specific for fungal enzymes involved in ergosterol biosynthesis, with no detectable effects on mammalian cholesterol biosynthesis in rat liver at the therapeutic concentration.
Morita
T
T
Department of Biochemistry, Gifu University School of Medicine, Japan.
Iwata
K
K
Nozawa
Y
Y
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002849:Chromatography, Gas; D003454:Cryptococcus / Q000187:drug effects*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000378:metabolism; D004875:Ergosterol / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D013185:Squalene / Q000378:metabolism; D013261:Sterols / Q000096:biosynthesis; D014047:Tolnaftate / Q000031:analogs & derivatives* / Q000494:pharmacology; D014249:Trichophyton / Q000187:drug effects* / Q000378:metabolism
D000935:Antifungal Agents; D013261:Sterols; D014047:Tolnaftate; D013185:Squalene; C060512:piritetrate; D004875:Ergosterol