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Antimicrobial Agents and Chemotherapy, January 2005, p. 126-130, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.126-130.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Buthionine Sulfoximine Increases the Toxicity of Nifurtimox and Benznidazole to Trypanosoma cruzi

Mario Faundez, Laura Pino, Paula Letelier, Carla Ortiz, Rodrigo López, Claudia Seguel, Jorge Ferreira, Mario Pavani, Antonio Morello, and Juan Diego Maya*

Program of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile

Received 16 July 2004/ Returned for modification 9 August 2004/ Accepted 5 September 2004

L-Buthionine (S,R)-sulfoximine (BSO) increased the toxicity of nifurtimox and benznidazole toward the epimastigote, trypomastigote, and amastigote forms of Trypanosoma cruzi. BSO at 500 µM decreased total glutathione-derived thiols by 70 to 80% in 48 h. In epimastigotes, 500 µM BSO decreased the concentration of nifurtimox needed to inhibit constant growth of the parasites by 50%, from 14.0 to 9.0 µM, and decreased that of benznidazole from 43.6 to 24.1 µM. The survival of epimastigotes or trypomastigotes treated with nifurtimox or benznidazole, as measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) reduction, was significantly decreased by 500 µM BSO. In Vero cells infected with amastigotes, 25 µM BSO was able to potentiate the effect of nifurtimox and benznidazole as measured by the percentage of infected Vero cells multiplied by the average number of intracellular amastigotes (endocytic index). At 0.5 µM nifurtimox, the proportion of Vero cells infected decreased from 27 to 20% and the endocytic index decreased from 2,500 to 980 when 25 µM BSO was added. Similar results were obtained with benznidazole- and BSO-benznidazole-treated cells. This study indicates that potentiation of nifurtimox or benznidazole by BSO could decrease the clinical dose of both drugs and diminish the side effects or the length of therapy.

* Corresponding author. Mailing address: University of Chile, Faculty of Medicine, Molecular and Clinical Pharmacology Program, P.O. Box 70000, Santiago 7, Chile. Phone: (562) 6786071. Fax: (562) 7355580. E-mail: jmaya{at}med.uchile.cl.

Antimicrobial Agents and Chemotherapy, January 2005, p. 126-130, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.126-130.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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