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Volume 272, Number 51, Issue of December 19, 1997 pp. 32709-32714
(Received for publication, August 22, 1997)
From the Department of Biochemistry, Merck Research Laboratories,
Rahway, New Jersey 07065
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
IC50 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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