Viridiofungins, Novel Inhibitors of Sphingolipid Synthesis.

Mandala, Suzanne; Thornton, Rosemary; Frommer, Beth R.; Dreikorn, Sarah; Kurtz, Myra B.

doi:10.7164/antibiotics.50.339

Cited by 77 publications

(51 citation statements)

References 13 publications

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“…In addition, the antifungal agent viridiofungin, previously recognized as an inhibitor of squalene synthase in vitro, has also been proved to be an inhibitor of SPT. [120] Other agents reduce SPT activity in cultured cells without directly inhibiting the enzyme. These include d-erythrosphingosine and the metabolically stable d-erythro-azidosphingosine, which reduces SPT activity in primary cultured neuronal cells either with the natural trans or the unnatural cis double bond.…”

Section: Inhibitors Of Serine Palmitoyltransferasementioning

confidence: 99%

Sphingolipids—Their Metabolic Pathways and the Pathobiochemistry of Neurodegenerative Diseases

Kolter

Sandhoff

1999

Angew. Chem. Int. Ed.

382

268

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Section: Inhibitors Of Serine Palmitoyltransferasementioning

confidence: 99%

Sphingolipids—Their Metabolic Pathways and the Pathobiochemistry of Neurodegenerative Diseases

Kolter

Sandhoff

1999

Angew. Chem. Int. Ed.

382

268

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“…Serine palmitoyltransferase, the first committed enzyme of sphingolipid synthesis in mammalian and fungal cells, condenses serine and palmitoylCoA to form the long chain sphingoid base, ketodihydrosphingosine. Several structurally diverse natural product inhibitors of this enzyme with antifungal activity have been discovered including sphingofungins (3,4), myriocin (5), lipoxamycins (6), and viridiofungins (7). Ketodihydrosphingosine is reduced to dihydrosphingosine and can be further modified to phytosphingosine in fungi and sphingosine in mammals.…”

mentioning

confidence: 99%

Rustmicin, a Potent Antifungal Agent, Inhibits Sphingolipid Synthesis at Inositol Phosphoceramide Synthase

Mandala

Thornton

Milligan

et al. 1998

Journal of Biological Chemistry

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110

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Rustmicin is a 14-membered macrolide previously identified as an inhibitor of plant pathogenic fungi by a mechanism that was not defined. We discovered that rustmicin inhibits inositol phosphoceramide synthase, resulting in the accumulation of ceramide and the loss of all of the complex sphingolipids. Rustmicin has potent fungicidal activity against clinically important human pathogens that is correlated with its sphingolipid inhibition. It is especially potent against Cryptococcus neoformans, where it inhibits growth and sphingolipid synthesis at concentrations <1 ng/ml and inhibits the enzyme with an IC 50 of 70 pM. This inhibition of the membrane-bound enzyme is reversible; moreover, rustmicin is nearly equipotent against the solubilized enzyme. Rustmicin was efficacious in a mouse model for cryptococcosis, but it was less active than predicted from its in vitro potency against this pathogen. Stability and drug efflux were identified as two factors limiting rustmicin's activity. In the presence of serum, rustmicin rapidly epimerizes at the C-2 position and is converted to a ␥-lactone, a product that is devoid of activity. Rustmicin was also found to be a remarkably good substrate for the Saccharomyces cerevisiae multidrug efflux pump encoded by PDR5.

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“…Three structurally distinct classes of inhibitors of serine palmitoyltransferase have been found: 1) the sphingofungin family, which includes sphingofungins A through F (4, 9) and myriocin/ISP1, which has immunosuppressant activity in addition to its antifungal activity (10); 2) the lipoxamycins, which are produced by actinomycetes (11); and 3) a newly described family of inhibitors called the viridiofungins (12). All of these compounds are very potent inhibitors (nanomolar to picomolar) of serine palmitoyltransferase, and though they kill a broad array of pathogenic fungi, they also inhibit the mammalian enzyme.…”

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confidence: 99%

Khafrefungin, a Novel Inhibitor of Sphingolipid Synthesis

Mandala

Thornton

Rosenbach

et al. 1997

Journal of Biological Chemistry

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127

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In the course of screening for antifungal agents we have discovered a novel compound isolated from an endophytic fungus that inhibits fungal sphingolipid synthesis. Khafrefungin, which is composed of aldonic acid linked via an ester to a C22 modified alkyl chain, has fungicidal activity against Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae. Sphingolipid synthesis is inhibited in these organisms at the step in which phosphoinositol is transferred to ceramide, resulting in accumulation of ceramide and loss of all of the complex sphingolipids. In vitro, khafrefungin inhibits the inositol phosphoceramide synthase of C. albicans with an IC 50 of 0.6 nM. Khafrefungin does not inhibit the synthesis of mammalian sphingolipids thus making this the first reported compound that is specific for the fungal pathway.

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Viridiofungins, Novel Inhibitors of Sphingolipid Synthesis.

Cited by 77 publications

References 13 publications

Sphingolipids—Their Metabolic Pathways and the Pathobiochemistry of Neurodegenerative Diseases

Sphingolipids—Their Metabolic Pathways and the Pathobiochemistry of Neurodegenerative Diseases

Rustmicin, a Potent Antifungal Agent, Inhibits Sphingolipid Synthesis at Inositol Phosphoceramide Synthase

Khafrefungin, a Novel Inhibitor of Sphingolipid Synthesis

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