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J Biol Chem, Vol. 273, Issue 24, 14942-14949, June 12, 1998
From the Department of Biochemistry, Merck Research Laboratories,
Rahway, New Jersey 07065
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 IC50 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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