Benznidazole-resistance in Trypanosoma cruzi: evidence that distinct mechanisms can act in concert.


Campos, MC; Leon, LL; Taylor, MC; Kelly, JM; (2014) Benznidazole-resistance in Trypanosoma cruzi: evidence that distinct mechanisms can act in concert. Molecular and biochemical parasitology, 193 (1). pp. 17-9. ISSN 0166-6851 DOI: 10.1016/j.molbiopara.2014.01.002

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Abstract

: Benznidazole is the main drug used to treat Trypanosoma cruzi infections. However, frequent instances of treatment failure have been reported. To better understand potential resistance mechanisms, we analysed three clones isolated from a single parasite population that had undergone benznidazole-selection. These clones exhibited differing levels of benznidazole-resistance (varying between 9 and 26-fold), and displayed cross-resistance to nifurtimox (2 to 4-fold). Each clone had acquired a stop-codon-generating mutation in the gene which encodes the nitroreductase (TcNTR) that is responsible for activating nitroheterocyclic pro-drugs. In addition, one clone had lost a copy of the chromosome containing TcNTR. However, these processes alone are insufficient to account for the extent and diversity of benznidazole-resistance. It is implicit from our results that additional mechanisms must also operate and that T. cruzi has an intrinsic ability to develop drug-resistance by independent sequential steps, even within a single population. This has important implications for drug development strategies.<br/>

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: Antimicrobial Resistance Centre (AMR)
PubMed ID: 24462750
Web of Science ID: 335427800003
URI: http://researchonline.lshtm.ac.uk/id/eprint/1496183

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