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A sphingolipid inhibitor induces a cytokinesis arrest and blocks stage differentiation in Giardia lamblia


Sonda, S; Stefanic, S; Hehl, A B (2008). A sphingolipid inhibitor induces a cytokinesis arrest and blocks stage differentiation in Giardia lamblia. Antimicrobial Agents and Chemotherapy, 52(2):563-569.

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.

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.

Citations

10 citations in Web of Science®
11 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Parasitology
04 Faculty of Medicine > Institute of Parasitology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
600 Technology
Language:English
Date:February 2008
Deposited On:18 Nov 2008 15:42
Last Modified:05 Apr 2016 12:32
Publisher:American Society for Microbiology
ISSN:0066-4804
Additional Information:Copyright: American Society for Microbiology
Publisher DOI:10.1128/AAC.01105-07
PubMed ID:18086854
Permanent URL: http://doi.org/10.5167/uzh-4856

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