Jatrophanes
from <i>Euphorbia squamosa</i> as Potent Inhibitors of <i>Candida albicans</i> Multidrug
Transporters
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Abstract
A series of structurally related
jatrophane diterpenoids
(<b>1</b>–<b>6</b>), including the new euphosquamosins
A–C (<b>4</b>–<b>6</b>), was purified from
the Iranian spurge <i>Euphorbia squamosa</i> and evaluated
for its capacity to inhibit drug efflux by multidrug transporters
of <i>Candida albicans</i>. Three of these compounds showed
an interesting profile of activity. In particular, deacetylserrulatin
B (<b>2</b>) and euphosquamosin C (<b>6</b>) strongly
inhibited the drug-efflux activity of the primary ABC-transporter <i>Ca</i>Cdr1p, an effect that translated, in a yeast strain overexpressing
this transporter, into an increased sensitivity to fluconazole.
These compounds were transported by <i>Ca</i>Cdr1p, as shown
by the observation of an 11–14-fold cross-resistance of yeast
growth, and could also inhibit the secondary MFS-transporter <i>Ca</i>Mdr1p. In contrast, euphosquamosin A (<b>4</b>) was selective for <i>Ca</i>Cdr1p, possibly as a result
of a different binding mode. Taken together, these observations suggest
jatrophane diterpenes to be a new class of potent inhibitors
of multidrug transporters critical for drug resistance in pathogenic
yeasts