Benznidazole-resistance in Trypanosoma cruzi: evidence that distinct mechanisms can act in concert.
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.
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK; Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, IOC, Avenida Brasil 4365, Manguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. Electronic address: monica.caroline@lshtm.ac.uk.
Mônica C O
MC
Campos
Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, IOC, Avenida Brasil 4365, Manguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. Electronic address: lleon@ioc.fiocruz.br.
Leonor L
LL
Leon
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Electronic address: martin.taylor@lshtm.ac.uk.
Martin C
MC
Taylor
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Electronic address: john.kelly@lshtm.ac.uk.
John M
JM
Kelly
D000981:Antiprotozoal Agents / Q000378:metabolism*; D018389:Codon, Nonsense; D004351:Drug Resistance; D017353:Gene Deletion; D009547:Nifurtimox / Q000378:metabolism; D009593:Nitroimidazoles / Q000378:metabolism*; D009601:Nitroreductases / Q000235:genetics; D021261:Parasitic Sensitivity Tests; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
D000981:Antiprotozoal Agents; D018389:Codon, Nonsense; D009593:Nitroimidazoles; D009601:Nitroreductases; D009547:Nifurtimox; C009999:benzonidazole
Benznidazole; Drug-resistance; Nitroreductase; Trypanosoma cruzi