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

Published online by Cambridge University Press:  15 November 2005

Marina V. Braga ,
Filippo Magaraci ,
Silvia Orenes Lorente ,
Ian Gilbert  and
Wanderley de Souza
Marina V. Braga
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, Ilha do Fundão, 21949-900, Rio de Janeiro-RJ, Brazil Departamento de Biologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21045-900, Rio de Janeiro-RJ, Brasil
Filippo Magaraci
Affiliation:
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, United Kingdom
Silvia Orenes Lorente
Affiliation:
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, United Kingdom
Ian Gilbert
Affiliation:
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, United Kingdom
Wanderley de Souza
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, Ilha do Fundão, 21949-900, Rio de Janeiro-RJ, Brazil
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Abstract

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.

Keywords

trypanosomatidmethyl transferasesterol biosynthesis inhibitorsergosterolchemotherapyultrastructure
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 11 , Issue 6 , December 2005 , pp. 506 - 515
Copyright
© 2005 Microscopy Society of America

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