A Locus of Resistance to Activation

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Science  11 Apr 2008:
Vol. 320, Issue 5873, pp. 157
DOI: 10.1126/science.320.5873.157c

Chagas' disease is caused by a protozoan parasite of the Trypanosomatidae, others of which cause a range of high-morbidity and disfiguring human diseases, usually within impoverished populations. Drug treatment takes several months, is expensive, and can have side effects. Moreover, the nitroheterocyclic compounds nifurtimox and benznidazole have been the frontline drugs for more than 40 years; nitroheterocycles do not act directly upon their targets, but must first be converted by endogenous enzymes to the active compounds.

Wilkinson et al. have worked out how these drugs are activated. Eight months of selection in vitro generated nitroheterocyclicresistant parasites that had lost a gene encoding a mitochondrially targeted type I nitroreductase, a flavoenzyme that reduces the nitro group and yields agents that damage DNA. Deleting a single copy of this gene enhanced resistance to nifurtimox and other nitroheterocycles severalfold. Intriguingly, knocking out both copies slowed replication and blocked differentiation into the infectious form of the parasite, which suggested that this enzyme is essential for parasite development in its mammalian host. — CA

Proc. Natl. Acad. Sci. U.S.A. 105, 5022 (2008).

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