Abstract

Sphingolipid biosynthesis pathways have recently emerged as a promising target for therapeutic intervention
against pathogens, including parasites. A key step in the synthesis of complex sphingolipids is the glucosylation
of ceramide, mediated by glucosylceramide (GlcCer) synthase, whose activity can be inhibited by PPMP
(1-phenyl-2-palmitoylamino-3-morpholino-1-propanol). In this study, we investigated whether PPMP inhibits
the proliferation and differentiation of the pathogenic parasite Giardia lamblia, the major cause of parasiteinduced
diarrhea worldwide. PPMP was found to block in vitro parasite replication in a dose-dependent
manner, with a 50% inhibitory concentration of 3.5 M. The inhibition of parasite replication was irreversible
at 10 MPPMP, a concentration that did not affect mammalian cell metabolism. Importantly, PPMP inhibited
the completion of cell division at a specific stage in late cytokinesis. Microscopic analysis of cells incubated with
PPMP revealed the aberrant accumulation of cellular membranes belonging to the endoplasmic reticulum
network in the caudal area of the parasites. Finally, PPMP induced a 90% reduction in G. lamblia differentiation
into cysts, the parasite stage responsible for the transmission of the disease. These results show that
PPMP is a powerful inhibitor of G. lamblia in vitro and that as-yet-uncharacterized sphingolipid biosynthetic
pathways are potential targets for the development of anti-G. lamblia agents.