A series of structurally related jatrophane
diterpenoids (1−6), including the new euphosquamosins A−
C (4−6), was purified from the Iranian spurge Euphorbia
squamosa and evaluated for its capacity to inhibit drug efflux by
multidrug transporters of Candida albicans. Three of these
compounds showed an interesting profile of activity. In
particular, deacetylserrulatin B (2) and euphosquamosin C
(6) strongly inhibited the drug-efflux activity of the primary
ABC-transporter CaCdr1p, an effect that translated, in a yeast
strain overexpressing this transporter, into an increased sensitivity to fluconazole. These compounds were transported by
CaCdr1p, as shown by the observation of an 11−14-fold cross-resistance of yeast growth, and could also inhibit the secondary
MFS-transporter CaMdr1p. In contrast, euphosquamosin A (4) was selective for CaCdr1p, 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.
