Effects of squalene epoxidase inhibitors on Candida albicans

Abstract

The relationship between sterol biosynthesis inhibition, membrane integrity, and cell growth inhibition in Candida albicans was examined for five squalene epoxidase inhibitors. The compounds were the thiocarbamates tolnaftate and tolciclate and the allylamines naftifine, terbinafine, and SDZ 87-469. All compounds inhibited sterol biosynthesis, with the concentrations that caused a 50% decrease in the total sterol-to-squalene ratio ranging from less than or equal to 0.01 microM for terbinafine and SDZ 87-469 to 500 microM for tolnaftate. At 100 microM, the compounds also caused up to a 30% release of intracellular [14C]aminoisobutyric acid. With terbinafine and SD2 87-469, aminoisobutyric acid release further increased in cells grown at concentrations that inhibited ergosterol biosynthesis. It is suggested that inhibition of ergosterol synthesis may render the C. albicans membrane susceptible to further damage, including direct damage from squalene epoxidase inhibitors.

The Mechanistic Targets of Antifungal Agents: An Overview

“…4 ) is described as a reversible, noncompetitive inhibition of squalene epoxidase [46], an enzyme, which together with (2,3)-oxidosqualene cyclase, is responsible for the cyclization of squalene to lanosterol. The resulting ergosterol depletion and squalene accumulation as indicated earlier affect membrane structure and functions, such as nutrient uptake [47, 48]. Allylamines such as naftifine and terbinafine along with tolnaftate, a thiocarbamate, have found utility as antifungal agents in the clinic [48].…”

Fenpropimorph affects uptake of uracil and cytosine in Saccharomyces cerevisiae

“…Reports from our laboratory and others indicate that fenpropimorph affects cellular metabolism through sites other than those for sterol biosynthesis (12,15), a mechanism which could contribute to growth inhibition of treated cells. Squalene epoxidase inhibitors (e.g., allylamines), a different class of sterol biosynthesis inhibitors, interfere with membrane integrity, possibly through combined effects on ergosterol levels and a separate unknown mechanism (8). In this article, we present evidence that fenpropimorph affects the uptake of Table 1.…”

Antibiotics inhibiting the biosynthesis of cholesterol (a review)

“…Some of these drugs (itraconazole) were reported to simultaneously suppress the NADPH-dependent 3-ketosteroidal reductase [103]. The activity of squalene epoxidase and some other enzymes involved in the final stages of CS biosynthesis can be also inhibited by allylamines, thiocarbamates, and 6-amino-2-pentylthiobenzothiazole [99,101 ].…”

“…Until recently, the group of known compounds inhibiting the late stages of sterol biosynthesis included, besides ricinolic and phytanic fatty acids [98], only the products of chemical synthesis, predominantly azoles [99][100][101]. The action of these compounds (clotrimazole, ketoconazole, itraconazole, fluconazole) reduces for the most part to suppressing the cytochrome P-450 dependent lanosterol 14ct-demethylase [100,102,103].…”