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Antimicrobial Agents and Chemotherapy, February 2008, p. 563-569, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01105-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Sphingolipid Inhibitor Induces a Cytokinesis Arrest and Blocks Stage Differentiation in Giardia lamblia{triangledown}

Sabrina Sonda,* Sasa Stefanic, and Adrian B. Hehl

Institute of Parasitology, University of Zurich, CH-8057 Zurich, Switzerland

Received 22 August 2007/ Returned for modification 24 October 2007/ Accepted 29 November 2007

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 parasite-induced diarrhea worldwide. PPMP was found to block in vitro parasite replication in a dose-dependent manner, with a 50% inhibitory concentration of 3.5 µM. The inhibition of parasite replication was irreversible at 10 µM PPMP, 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.

* Corresponding author. Mailing address: Institute of Parasitology, University of Zurich, Winterthurerstrasse 266a, CH-8057 Zurich, Switzerland. Phone: 41-1-635-8514. Fax: 41-1-635-8907. E-mail: sabrina.sonda{at}vetparas.uzh.ch

{triangledown} Published ahead of print on 17 December 2007.

Antimicrobial Agents and Chemotherapy, February 2008, p. 563-569, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01105-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hernandez, Y., Shpak, M., Duarte, T. T., Mendez, T. L., Maldonado, R. A., Roychowdhury, S., Rodrigues, M. L., Das, S. (2008). Novel Role of Sphingolipid Synthesis Genes in Regulating Giardial Encystation. Infect. Immun. 76: 2939-2949 [Abstract] [Full Text]  


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