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A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes

Summary: A mechanism for cross-resistance to nifurtimox
and benznidazole in trypanosomes
Shane R. Wilkinson*
, Martin C. Taylor
, David Horn
, John M. Kelly
, and Ian Cheeseman
*School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, United Kingdom; and Department of Infectious
and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom
Edited by P. Borst, The Netherlands Cancer Institute, Amsterdam, The Netherlands, and approved February 12, 2008 (received for review
November 21, 2007)
Nifurtimox and benznidazole are the front-line drugs used to treat
Chagas disease, the most important parasitic infection in the Amer-
icas. These agents function as prodrugs and must be activated within
the parasite to have trypanocidal effects. Despite >40 years of
research, the mechanism(s) of action and resistance have remained
elusive. Here, we report that in trypanosomes, both drugs are acti-
vated by a NADH-dependent, mitochondrially localized, bacterial-like,
type I nitroreductase (NTR), and that down-regulation of this explains
how resistance may emerge. Loss of a single copy of this gene in


Source: Arnold, Jonathan - Nanoscale Science and Engineering Center & Department of Genetics, University of Georgia


Collections: Biotechnology