Jatrophanes from <i>Euphorbia squamosa</i> as Potent Inhibitors of <i>Candida albicans</i> Multidrug Transporters

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