Inhibition of Inositol Phosphorylceramide Synthase by Aureobasidin A in Candida and Aspergillus Species

Abstract

Inositol phosphorylceramide (IPC) synthase is an enzyme common to fungi and plants that catalyzes the transfer of phosphoinositol from phosphatidylinositol to ceramide to form IPC. The reaction is a key step in fungal sphingolipid biosynthesis and the target of the antibiotics galbonolide A, aureobasidin A, and khafrefungin. As a first step toward understanding the antifungal spectrum of IPC synthase inhibitors, we examined the sensitivity of IPC synthase to aureobasidin A in membrane preparations of Candida species (Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei) and Aspergillus species (Aspergillus fumigatus, A. flavus, A. niger, and A. terreus). As expected, preparations from the five Candida species, all exquisitely susceptible to aureobasidin A (MICs, <2 g/ml), had IPC synthase activity (specific activity, 50 to 400 pmol/min/ mg of protein) sensitive to aureobasidin A (50% inhibitory concentrations [IC 50 s], 2 to 4 ng/ml). Surprisingly, preparations from the four Aspergillus species, including A. fumigatus and A. flavus, which are intrinsically resistant to aureobasidin A (MICs, >50 g/ml), had IPC synthase activity (specific activity, 1 to 3 pmol/min/mg of protein) also sensitive to aureobasidin A (IC 50 s, 3 to 5 ng/ml). The mammalian multidrug resistance modulators verapamil, chlorpromazine, and trifluoperazine lowered the MIC of aureobasidin A for A. fumigatus from >50 g/ml to 2 to 3 g/ml, suggesting that the resistance of this major fungal pathogen is the result of increased efflux.

Newly Discovered Neutral Glycosphingolipids in Aureobasidin A-resistant Zygomycetes

“…As shown in Fig. 1A, AbA strongly inhibits the growth of filamentous fungi such as A. oryzae, P. oxalicum, and Acremonium sp., previously reported for the yeast Saccharomyces cerevisiae (W303-1A) and other fungi (7)(8)(9)(10)13). However, growth inhibition by AbA was not observed for any Zygomycetes species such as M. hiemalis, R. microsporus, R. pusillus, and A. corymbifera (Fig.…”

“…Aureobasidin A is well known and widely used as an antifungal agent for Eumycetes including yeasts and fungi. It exhibits strong fungicidal activity against many pathogenic fungi, including Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus (7,8). Recent studies (6) have shown that this antifungal agent inhibits IPC synthase in fungal cells.…”

Characterization of inositol phosphorylceramides from Leishmania major by tandem mass spectrometry with electrospray ionization

“…In contrast to fungi and plants, mammalian cells do not synthesize IPC or GIPCs; instead, choline phosphate is transferred from phosphatidylcholine to the 1-OH group of ceramide, leading to the synthesis of sphingomyelin (SM). This difference in SL metabolism between mammalian cells and fungi represents an attractive target for antifungal drugs such as khafrefungin [15] and aureobasidin A [14,16], which specifically inhibit the IPC synthase.…”

Antagonistic yeasts competes for iron with winter wheat stem base pathogens

“…A. pullulans can also produce aureobasidins, polypeptide substances showing fungicidal action, which inhibit the growth of species of the genus Aspergillus (Prasongsuk et al 2013). Aureobasidins are a family of cyclic depsipeptide antibiotics with 18 known derivatives (aureobasidin A to R) that differ in their amino acid composition (Prasongsuk et al 2013;Ikai et al 1991) and are known to inhibit inositol phosphoacrylamide synthase, a key enzyme for fungal sphingolipid synthesis (Zhong et al 2000).…”