Antifungals targeted to sphingolipid synthesis: focus on inositol phosphorylceramide synthase

Currently available antifungal drugs for serious infections have essentially two molecular targets, 14alpha demethylase (azoles) and ergosterol (polyenes). The former is a fungistatic target, vulnerable to resistance development; the latter, while a fungicidal target, is not sufficiently different from the host to ensure high selectivity. Antifungals in clinical development have a third molecular target, beta-1,3-glucan synthase. Drugs aimed at totally new targets are required to increase our chemotherapeutic options and to forestall, alone or in combination chemotherapy, the emergence of drug resistance. Sphingolipids, essential membrane components in eukaryotic cells, but distinct in mammalian and fungal cells, present an attractive new target. Several natural product inhibitors of sphingolipid biosynthesis have been discovered in recent years, some of which act at a step unique to fungi and have potent and selective antifungal activity.