Sphingolipids as Targets for Treatment of Fungal Infections

Abstract

Invasive fungal infections have significantly increased in the last few decades. Three classes of drugs are commonly used to treat these infections: polyenes, azoles and echinocandins. Unfortunately each of these drugs has drawbacks; polyenes are toxic, resistance against azoles is emerging and echinocandins have narrow spectrum of activity. Thus, the development of new antifungals is urgently needed. In this context, fungal sphingolipids have emerged as a potential target for new antifungals, because their biosynthesis in fungi is structurally different than in mammals. Besides, some fungal sphingolipids play an important role in the regulation of virulence in a variety of fungi. This review aims to highlight the diverse strategies that could be used to block the synthesis or/and function of fungal sphingolipids.

Nuclear magnetic resonance solution structure of Pisum sativum defensin 2 provides evidence for the presence of hydrophobic surface‐clusters

“…necessary for virulence and defensin recognition. 9,10 This same lipid target was described to be root for other PDs, as Psd1 and RsAFP2. 11,12 Antimicrobial peptides are regarded as potential targets for the development of novel therapeutics drugs mainly due to antimicrobial resistance.…”

“…The antifungal mechanism of Ps d2 is not fully understood, but α‐OH‐Δ4,Δ8‐9,methyl‐glucosylceramide, a glycosphingolipid present in fungal membranes, plays a key role for the peptide‐interaction . Sphingolipids also play an essential role in controlling fungal virulence and a particular structure is necessary for virulence and defensin recognition . This same lipid target was described to be root for other PDs, as Ps d1 and Rs AFP2 …”

The antifungal pipeline: a reality check

“…Sphingolipids are important in cellular metabolism but can also be important in the regulation of the fungal virulence composite. There are now diverse strategies that could be used to block the synthesis and/or function of sphingolipids 43 . Several new compounds ( N ′-(3-bromo-4-hydroxybenzylidene)-2-methyl benzohydrazide and its derivative, 3-bromo- N ′-(3-bromo-4-hydroxybenzylidene) benzohydrazide) have been found to selectively decrease levels of fungal glycosphingolipids relative to the mammalian ones.…”

Analysis of sphingolipids, sterols, and phospholipids in human pathogenic Cryptococcus strains

“…4) The small sphingolipid molecules, sphingosine (Sph), dihydrosphingosine (dhSph), sphingosine-1-phosphate (Sph1P), and dhSph-1-phosphate (dhSph1P), have an important role in modulation of host immune response toward Cryptococcus infection (26,27). Altogether, these published reports by our group and others have emphasized the significance of the sphingolipid biosynthetic pathway for the development inhibitors as treatment strategies against Cryptococcus (28,29).…”

“…Lipid biosynthetic pathways have been a major resource in the development treatment measures for cryptococcal infections (28). The antifungals, amphotericin B (a polyene) and fluconazole (an azole), are commonly used for targeting fungal ergosterol biosynthesis (30).…”