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

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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, 50 μg/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 μg/ml to 2 to 3 μg/ml, suggesting that the resistance of this major fungal pathogen is the result of increased efflux.