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High-throughput screening in suboptimal growth conditions identifies agonists of Giardia lamblia proliferation

Published online by Cambridge University Press:  10 August 2010

Z. FAGHIRI ,
R. BONILLA SANTIAGO ,
Z. WU  and
G. WIDMER
Z. FAGHIRI
Affiliation:
Tufts Cummings School of Veterinary Medicine, 200 Westboro Road, North Grafton, Massachusetts, USA
R. BONILLA SANTIAGO
Affiliation:
Tufts Cummings School of Veterinary Medicine, 200 Westboro Road, North Grafton, Massachusetts, USA
Z. WU
Affiliation:
Brown University, Center for Statistical Sciences, Providence, Rhode Island, USA
G. WIDMER*
Affiliation:
Tufts Cummings School of Veterinary Medicine, 200 Westboro Road, North Grafton, Massachusetts, USA
*
*Corresponding author: Tufts Cummings School of Veterinary Medicine, 200 Westboro Road, North Grafton, MA 01536, USA. Tel: +508 839 7944. Fax: +508 839 7911. E-mail: [email protected]
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Summary

Giardia lamblia is one of the most prevalent parasites of mankind and is estimated to cause over 200 million infections per year. To screen chemical libraries for compounds that perturb trophozoite proliferation we adapted a conventional culture method to 384-well plates and identified numerous inhibitors. Here we used a modified assay to screen for compounds that promote trophozoite multiplication. Trophozoite growth was reduced by dilution of the culture medium and the growth period was extended to screen 2 compound libraries comprising 1500 compounds. A total of 4 agonists of trophozoite multiplication were identified. In the presence of one of these compounds, strychnine, enhanced growth was accompanied by unusual trophozoite morphology characterized by dividing trophozoites displaying more than the 2 nuclei per cell which are normally observed. The other agonists, although belonging to 2 distinct chemical groups, are known to affect isoprenylation, indicating a link between protein or lipid isoprenylation and growth in culture. Although inhibitors of isoprenylation are known to antagonize proliferation of mammalian cells, an agonistic effect of isoprenylation modulators has to our knowledge not been described previously. These observations illustrate the power of chemical genetics for identifying pathways controlling specific traits in G. lamblia.

Keywords

Giardia lambliatrophozoite proliferationagonistisoprenylation
Type
Research Article
Information
Parasitology , Volume 138 , Issue 2 , February 2011 , pp. 194 - 200
Copyright
Copyright © Cambridge University Press 2010

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