Fungal sphingolipids: role in the regulation of virulence and potential as targets for future antifungal therapies

ABSTRACT

Introduction

The antifungal therapy currently available includes three major classes of drugs: polyenes, azoles and echinocandins. However, the clinical use of these compounds faces several challenges: while polyenes are toxic to the host, antifungal resistance to azoles and echinocandins has been reported.

Areas covered

Fungal sphingolipids (SL) play a pivotal role in growth, morphogenesis and virulence. In addition, fungi possess unique enzymes involved in SL synthesis, leading to the production of lipids which are absent or differ structurally from the mammalian counterparts. In this review, we address the enzymatic reactions involved in the SL synthesis and their relevance to the fungal pathogenesis, highlighting their potential as targets for novel drugs and the inhibitors described so far.

Expert opinion

The pharmacological inhibition of fungal serine palmitoyltransferase depends on the development of specific drugs, as myriocin also targets the mammalian enzyme. Inhibitors of ceramide synthase might constitute potent antifungals, by depleting the pool of complex SL and leading to the accumulation of the toxic intermediates. Acylhydrazones and aureobasidin A, which inhibit GlcCer and IPC synthesis, are not toxic to the host and effectively treat invasive mycoses, emerging as promising new classes of antifungal drugs.

KEYWORDS:

• Fungi
• sphingolipids
• antifungal therapy
• glucosylceramide
• inositol phosphorylceramide

Article highlights

• Fungal sphingolipids play a crucial role in growth and virulence.

• The unique structure of fungal sphingolipids makes them promising targets for drug development.

• Novel inhibitors of ceramide synthases might act as potent drugs, by depleting the pool of complex sphingolipids and leading to the accumulation of toxic intermediates.

• Promising compounds for clinical trials include acylhydrazones and aureobasidin A, which inhibit the production of glucosylceramide and IPC, efficiently treating invasive fungal infections.

Declaration of interest

M. Del Poeta is a cofounder and Chief Scientific Officer (CSO) of MicroRid Technologies, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by NIH grants AI116420, AI125770 and AI136934 to M. Del Poeta and by Merit Review grant I01BX002624 from the Veterans Affairs Program to M. Del Poeta.