Table 1.
Candidate drugs targeting sphingolipids
| Drugs | Advantages | Disadvantages |
|---|---|---|
|
| ||
| Targeting the biosynthesis of fungal sphingolipids (inhibitors of sphingolipid-metabolizing enzymes) | ||
|
| ||
| SPT inhibitors (myriocin, sphingofungin) | Impair biofilm formation; effective against Candida and Aspergillus spp. | Toxic to host; enhance the mortality of host |
| Ceramide synthase inhibitors (australifungin, fumonisin B1) | Have broad spectrum of antifungal effect against Candida and Aspergillus spp. as well as Cryptococcus neoformans | Toxic to host; lack specificity |
| Inhibitors of S1P, sphingosine kinases and S1P lyase | Highly toxic to fungi; improve the host immune response | No drugs exist till now |
| IPC inhibitors (aureobasidin, galbonolide, khafrefungin, rustmicin) | Active against Candida albicans and C. neoformans; impair biofilm formation; Ipc1 is not present in human cells | Lack antifungal effect against mold, such as Aspergillus spp. |
| GlcCer synthase inhibitors (D-threo-PDMP) | Have antifungal effect against Aspergillus fumigatus and Aspergillus nidulans | Toxic to host; off-target effect; have no significant effect against C. neoformans |
| GlcCer inhibitors (BHBM, D0) | Show antifungal activity against Candida spp., C. neoformans, A. fumigatus and Histoplasma capsulatum in vitro and in vivo; well tolerated in animal model | Require further study |
|
| ||
| Targeting the function of sphingolipids directly (targeting GlcCer directly) | ||
|
| ||
| RsAFP2 (defensins) | Have no cross interactions with human GlcCer; active against C. albicans; impair the transition from yeast to hyphae | Strains lacking GlcCer synthase gene are resistant to RsAFP2 (such as Candida glabrata) |
| Monoclonal antibodies against GlcCer | Inhibit conidia germination; facilitate phagocytosis by activating macrophages; present a synergistic effect with other antifungals | Antifungal spectrum is relatively narrow |
Abbreviations: BHBM, N′-(3-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide; D-threo-PDMP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; D0, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide; GlcCer, glucosylceramide; IPC, inositolphosphoryl ceramide; S1P, sphingosine-1-phosphate; SPT, serine palmitoyltransferase.