Fungal phospholipid metabolism for antifungal drug discovery

Abstract

Invasive fungal infections often respond poorly to antifungal drugs. The fungal invasin phospholipase B (PLB) and/or its biosynthetic pathway are novel targets for drug development. Compounds with structural similarities to phosphatidylcholine, which is a preferred substrate of cryptococcal PLB1, were purchased or synthesised. For many, there was a correlation between antifungal and anti-PLB activity but not all demonstrated selectivity for fungal compared with mammalian phospholipase, and some were toxic to mammalian cells in culture. The most promising, a bis-pyridinium compound, is undergoing toxicity testing in mice. Miltefosine (MI), a stable phospholipid analogue used in the treatment of leishmaniasis also has broad spectrum fungicidal activity, but inhibition of PLB is not its major mode of action. To improve antifungal potency and reduce toxicity of MI, analogues of this alkyl phospholipid have been synthesised and are under investigation.