An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs.


Voak, AA; Gobalakrishnapillai, V; Seifert, K; Balczo, E; Hu, L; Hall, BS; Wilkinson, SR; (2013) An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs. The Journal of biological chemistry, 288 (40). pp. 28466-76. ISSN 0021-9258 DOI: https://doi.org/10.1074/jbc.M113.494781

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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.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Leishmaniasis Group
Neglected Tropical Diseases Network
PubMed ID: 23946481
Web of Science ID: 330298800005
URI: http://researchonline.lshtm.ac.uk/id/eprint/1694870

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