Benznidazole is the frontline drug used against Trypanosoma cruzi, the causative agent of Chagas disease. However, treatment failures are often reported. Here, we demonstrate that independently acquired mutations in the gene encoding a mitochondrial nitroreductase (TcNTR) can give rise to distinct drug-resistant clones within a single population. Following selection of benznidazole-resistant parasites, all clones examined had lost one of the chromosomes containing the TcNTR gene. Sequence analysis of the remaining TcNTR allele revealed 3 distinct mutant genes in different resistant clones. Expression studies showed that these mutant proteins were unable to activate benznidazole. This correlated with loss of flavin mononucleotide binding. The drug-resistant phenotype could be reversed by transfection with wild-type TcNTR. These results identify TcNTR as a central player in acquired resistance to benznidazole. They also demonstrate that T. cruzi has a propensity to undergo genetic changes that can lead to drug resistance, a finding that has implications for future therapeutic strategies.
Pharmacology, Toxicology and Pharmaceutical Science
12
6%
Other
15
8%
Unknown
73
38%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 January 2023.
All research outputs
#11,232,415
of 34,363,559 outputs
Outputs from Journal of Infectious Diseases
#10,369
of 18,978 outputs
Outputs of similar age
#72,666
of 212,475 outputs
Outputs of similar age from Journal of Infectious Diseases
#80
of 152 outputs
Altmetric has tracked 34,363,559 research outputs across all sources so far. This one has received more attention than most of these and is in the 66th percentile.
So far Altmetric has tracked 18,978 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 17.0. This one is in the 44th percentile – i.e., 44% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 212,475 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 65% of its contemporaries.
We're also able to compare this research output to 152 others from the same source and published within six weeks on either side of this one. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.
