Structural and enzymatic insights into species-specific resistance to schistosome parasite drug therapy.

The antischistosomal prodrug oxamniquine is activated by a sulfotransferase (SULT) in the parasitic flatworm Of the three main human schistosome species, only is sensitive to oxamniquine therapy despite the presence of SULT orthologs in and The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of and SULTs, including SULT in complex with oxamniquine. We also examined the activity of the three enzymes ; surprisingly, all three are active toward oxamniquine, yet we observed differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results provide guidance for designing oxamniquine derivatives to treat infection caused by all species of schistosome to combat emerging resistance to current therapy.