ArticleThe Journal of biological chemistry2013
An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 3: from lead towards a drug development candidate.The Journal of antimicrobial chemotherapy · 2026Review
- Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase.International journal for parasitology. Drugs and drug resistance · 2025Article
- Free Radical Production Induced by Nitroimidazole Compounds Lead to Cell Death inMolecules (Basel, Switzerland) · 2024Article
- Heterologous Expression and Characterization of a Full-length Protozoan Nitroreductase from Leishmania orientalis isolate PCM2.Molecular biotechnology · 2023Article
- Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates.Biomolecules · 2023Review
- Article
- Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity.International journal of molecular sciences · 2021Review
- Nitroaromatic Antibiotics as Nitrogen Oxide Sources.Biomolecules · 2021Review
- Article
- A Multi-Species Phenotypic Screening Assay for Leishmaniasis Drug Discovery Shows That Active Compounds Display a High Degree of Species-Specificity.Molecules (Basel, Switzerland) · 2020Article
- In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria.BMC microbiology · 2020Article
- Nongenotoxic 3-Nitroimidazo[1,2-ACS medicinal chemistry letters · 2019Article
- 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.European journal of medicinal chemistry · 2018Article
- Distinct activation mechanisms trigger the trypanocidal activity of DNA damaging prodrugs.Molecular microbiology · 2017Article
- Identification of a type I nitroreductase gene in non-virulent Trypanosoma rangeli.Memorias do Instituto Oswaldo Cruz · 2017Article
- Heterologous Overexpression and Biochemical Characterization of a Nitroreductase from Gluconobacter oxydans 621H.Molecular biotechnology · 2016Article
- Comparative characterisation of two nitroreductases from Giardia lamblia as potential activators of nitro compounds.International journal for parasitology. Drugs and drug resistance · 2015Article
- Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects.Trends in parasitology · 2014Review
- Protein engineering: a new frontier for biological therapeutics.Current drug metabolism · 2014Review
- Evaluating aziridinyl nitrobenzamide compounds as leishmanicidal prodrugs.Antimicrobial agents and chemotherapy · 2014Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nitroaromatic prodrugs are used to treat a range of microbial infections with selectivity achieved by specific activation reactions. For trypanosomatid parasites, this is mediated by type I nitroreductases. Here, we demonstrate that the causative agent of leishmaniasis, Leishmania major, expresses an FMN-containing nitroreductase (LmNTR) that metabolizes a wide range of substrates, and based on electron donor and acceptor preferences, it may function as an NADH:quinone oxidoreductase. Using gene deletion approaches, we demonstrate that this activity is essential to L. major promastigotes, the parasite forms found in the insect vector. Intriguingly, LmNTR(+/-) heterozygote promastigote parasites could readily differentiate into infectious metacyclic cells but these were unable to establish infections in cultured mammalian cells and caused delayed pathology in mice. Furthermore, we exploit the LmNTR activity evaluating a library of nitrobenzylphosphoramide mustards using biochemical and phenotypic screens. We identify a subset of compounds that display significant growth inhibitory properties against the intracellular parasite form found in the mammalian hosts. The leishmanicidal activity was shown to be LmNTR-specific as the LmNTR(+/-) heterozygote promastigotes displayed resistance to the most potent mustards. We conclude that LmNTR can be targeted for drug development by exploiting its prodrug activating property or by designing specific inhibitors to block its endogenous function.
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