ELO2 and ELO3, homologues of the Saccharomyces cerevisiae ELO1 gene, function in fatty acid elongation and are required for sphingolipid formation

Chemistry and Biology of Mycotoxins and Related Fungal Metabolites

During the past two decades the frequencies and types of life-threatening fungal infections have increased dramatically in immunocompromised patients (7, 220, 232, 282). Several factors have contributed to this rise: the expansion of severely ill and/or immunocompromised patient populations with human immunodeficiency virus (HIV) infection, with chemotherapy-induced neutropenia, and receiving organ transplant-associated immunosuppressive therapy; more invasive medical procedures, such as extensive surgery and the use of prosthetic devices and vascular catheters; treatment with broad-spectrum antibiotics or glucocorticosteroids; parenteral nutrition; and peritoneal dialysis or hemodialysis (25, 63, 66). The major opportunistic pathogen has been Candida albicans (17, 25, 142); however, the frequency of non-C. albicans Candida species is increasing (232, 287). Invasive pulmonary aspergillosis is a leading cause of attributable mortality in bone marrow transplant recipients (209). HIV-infected patients are particularly susceptible to mucosal candidiasis, cryptococcal meningitis, disseminated histoplasmosis, and coccidioidomycosis (5, 66, 294), while Pneumocystis carinii pneumonia is a leading cause of death in HIV-infected patients in North America and Europe (121). P. carinii was considered, until recently, a protozoal parasite on the basis of its resistance to classical antifungal agents. However, it has been reclassified as being most closely related to ascomycetous fungi on the basis of rRNA and b-tubulin homologies, the presence of the typical fungal cell wall polymers glucan and chitin, and separate dihydrofolate reductase and thymidylate synthase enzymes (in protozoa, both activities reside on a single protein) (74, 163). Treatment of invasive mycoses is complicated by problems in diagnosis (285) and susceptibility testing (8, 79, 90, 230) of fungi. Opportunistic fungal infections are often treated empirically in profoundly neutropenic patients when there is fever of unknown origin refractory to broad-spectrum antibacterial agents (233, 266, 284). Treatment of deeply invasive fungal infections has consistently lagged behind bacterial chemotherapy (27, 178). Amphotericin B, still the ‘‘gold standard’’ for the treatment of most severe invasive fungal infections, was discovered in 1956 (102). One reason for the slow progress is that, like mammalian cells, fungi are eukaryotes, and thus, agents that inhibit protein, RNA, or DNA biosynthesis have greater potential for toxicity. A second reason is that, until recently, the incidence of life-threatening fungal infections was perceived as being too low to warrant aggressive research by the pharmaceutical industry. In the past decade, however, there has been a major expansion in the number of antifungal drugs available (99). Nevertheless, there are still major weaknesses in their spectra, potencies, safety, and pharmacokinetic properties. This minireview briefly discusses the antifungal agents currently in clinical use. It then considers the use of promising new biochemical targets in fungi as well as host-based, immunological approaches as evolving strategies for antifungal therapy.

Antifungal agents: chemotherapeutic targets and immunologic strategies.

Physiology and pathophysiology of sphingolipid metabolism and signaling.

Sphingolipid metabolism in metazoan cells consists of a complex interconnected web of numerous enzymes, metabolites and modes of regulation. At the centre of sphingolipid metabolism reside CerSs (ceramide synthases), a group of enzymes that catalyse the formation of ceramides from sphingoid base and acyl-CoA substrates. From a metabolic perspective, these enzymes occupy a unique niche in that they simultaneously regulate de novo sphingolipid synthesis and the recycling of free sphingosine produced from the degradation of pre-formed sphingolipids (salvage pathway). Six mammalian CerSs (CerS1–CerS6) have been identified. Unique characteristics have been described for each of these enzymes, but perhaps the most notable is the ability of individual CerS isoforms to produce ceramides with characteristic acyl-chain distributions. Through this control of acyl-chain length and perhaps in a compartment-specific manner, CerSs appear to regulate multiple aspects of sphingolipid-mediated cell and organismal biology. In the present review, we discuss the function of CerSs as critical regulators of sphingolipid metabolism, highlight their unique characteristics and explore the emerging roles of CerSs in regulating programmed cell death, cancer and many other aspects of biology.

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Ceramide synthases at the centre of sphingolipid metabolism and biology

Potent antifungal activity was detected in fermentation extracts of Sporormiella australis and two related components were isolated from solid fermentations using silica gel and high speed countercurrent chromatography. The most active antifungal component, australifungin, contained a unique combination of alpha-diketone and beta-ketoaldehyde functional groups. Australifungin exhibited broad spectrum antifungal activity against human pathogenic fungi with MICs against Candida spp., Cryptococcus neoformans, and Aspergillus spp. between 0.015 and 1.0 microgram/ml. Mode of action studies revealed that australifungin interfered with fungal lipid metabolism by specifically inhibiting sphingolipid synthesis at the step converting sphinganine to ceramide.

The discovery of australifungin, a novel inhibitor of sphinganine N-acyltransferase from Sporormiella australis. Producing organism, fermentation, isolation, and biological activity.

In screening for antifungal inhibitors from fungi, four related antifungal agents have been isolated from the cultivation of Aspergillus fumigatus ATCC 20857. These agents were initially produced by the microorganism growing on a solid millet-based medium. A liquid medium containing both glucose and glycerol has also been developed in which these antibiotics are produced in two phases. These novel compounds, sphingofungins A, B, C, and D, show a limited spectrum of antifungal activity but were especially effective against Cryptococcus species.

Sphingofungins A, B, C, and D; A new family of antifungal agents. I. Fermentation, isolation, and biological activity

This invention relates to a method of inhibiting fungal growth by employing an antifungal amount of a compound of formula (I): ##STR1##

Novel anti-fungal compounds

Compound of formulae (I) and (II) are HMG-CoA synthase inhibitors and exhibit antifungal activity. ##STR1##

Novel hmg-coa synthase inhibitors

The Discovery of Australifungin, a Novel Inhibitor of Sphinganine N‐ Acyltransferase from Sporormiella australis. Producing Organism, Fermentation, Isolation, and Biological Activity.

Walter Rozdilsky

Papers

The discovery of australifungin, a novel inhibitor of sphinganine N-acyltransferase from Sporormiella australis. Producing organism, fermentation, isolation, and biological activity.

Sphingofungins A, B, C, and D; A new family of antifungal agents. I. Fermentation, isolation, and biological activity

Novel anti-fungal compounds

Novel hmg-coa synthase inhibitors

The Discovery of Australifungin, a Novel Inhibitor of Sphinganine N‐ Acyltransferase from Sporormiella australis. Producing Organism, Fermentation, Isolation, and Biological Activity.