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JAC Advance Access originally published online on January 28, 2009
Journal of Antimicrobial Chemotherapy 2009 63(3):469-472; doi:10.1093/jac/dkn546
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Altered sterol profile induced in Leishmania amazonensis by a natural dihydroxymethoxylated chalcone

Eduardo Caio Torres-Santos1,2, Maria Isabel Sampaio-Santos3, Frederick S. Buckner4, Kohei Yokoyama5, Michael Gelb5, Julio A. Urbina6 and Bartira Rossi-Bergmann1,*

1 Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 2 Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil 3 Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 4 Department of Medicine, University of Washington, Seattle, WA, USA 5 Department of Chemistry, University of Washington, Seattle, WA, USA 6 Instituto Venezoelano de Investigaciones Científicas, Caracas, Venezuela

Received 11 August 2008; returned 15 October 2008; revised 29 November 2008; accepted 19 December 2008

* Corresponding author. Tel: +55-21-2260-6963; Fax: +55-21-2280-8193; E-mail: bartira{at}biof.ufrj.br

Objectives: The effects of the antileishmanial chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC) on Leishmania amazonensis sterol composition and biosynthesis were investigated to obtain information about the mechanism of growth inhibition by DMC on this parasite.

Methods: The interference of sterol biosynthesis by DMC was studied in drug-treated promastigotes by two different methods. (i) Newly synthesized sterols from parasites grown in the presence of [3H]mevalonate were analysed by thin layer chromatography (TLC)/fluorography. (ii) Total sterols extracted from the parasites grown with or without DMC were characterized by gas chromatography coupled to mass spectroscopy (GC/MS).

Results: TLC and GC/MS analyses of sterols extracted from DMC-treated promastigotes revealed the accumulation of early precursors and a reduction in the levels of C-14 demethylated and C-24 alkylated sterols, as well as a reduction in exogenous cholesterol uptake.

Conclusions: This study demonstrates that the natural chalcone DMC alters the sterol composition of L. amazonensis and suggests that the parasite target is different from other known sterol inhibitors.

Keywords: lipid metabolism , cholesterol , ketoconazole , Trypanosoma


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