Effects of Inhibitors of Δ24(25)-Sterol Methyl Transferase on the Ultrastructure of Epimastigotes of Trypanosoma cruzi

Trypanosoma cruzi is the ethiological agent of Chagas disease. New compounds are being developed based on the biosynthesis and function of sterols, because T. cruzi has a requirement for specific endogenous sterols for growth and survival. Sterol biosynthesis inhibitors (SBIs) are drugs commonly use...

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Published inMicroscopy and microanalysis Vol. 11; no. 6; pp. 506 - 515
Main Authors Braga, Marina V., Magaraci, Filippo, Lorente, Silvia Orenes, Gilbert, Ian, de Souza, Wanderley
Format Journal Article
LanguageEnglish
Published New York, USA Cambridge University Press 01.12.2005
Subjects
Biological Applications
trypanosomatid
sterol biosynthesis inhibitors
methyl transferase
ultrastructure
chemotherapy
ergosterol
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Summary:Trypanosoma cruzi is the ethiological agent of Chagas disease. New compounds are being developed based on the biosynthesis and function of sterols, because T. cruzi has a requirement for specific endogenous sterols for growth and survival. Sterol biosynthesis inhibitors (SBIs) are drugs commonly used against fungal diseases. These drugs act by depleting essential and specific membrane components and/or inducing the accumulation of toxic intermediary or lateral products of the biosynthetic pathway. In this work we present the effects of WSP488, WSP501, and WSP561, specific inhibitors of Δ24(25)-sterol methyl transferase, on the ultrastructure of T. cruzi epimastigotes. All three drugs inhibited parasite multiplication at low concentrations, with IC50 values of 0.48, 0.44, and 0.48 μM, respectively, and induced marked morphological changes including (a) blockage of cell division; (b) swelling of the mitochondrion, with several projections and depressions; (c) swelling of the perinuclear space; (d) presence of autophagosomes and myelin-like figures; (e) enlargement of the flagellar pocket and of a cytoplasmic vacuole located in close association with the flagellar pocket; (f) detachment of the membrane of the cell body; and (g) formation of a vesicle at the surface of the parasite between the flagellar pocket and the cytostome. Our results show that these drugs are potent in vitro inhibitors of growth of T. cruzi.
ISSN:1431-9276
1435-8115
DOI:10.1017/S143192760505035X