Summary
The current therapeutic modalities for visceral leishmaniasis (VL) are plagued with the limited availability of antileishmanial compounds coupled with an alarming increase in nonresponsiveness to conventional antimonial therapy. Studies pertaining to the mechanism(s) by which Leishmania spp. acquire resistance to antimony is a subject of intense research. It has been demonstrated to be multifactorial phenomena and include alterations in drug influx, drug metabolism, thiol metabolism, and drug efflux. In antimony-resistant strains, the availability of antimony (Sb) is impeded by the diminished conversion of pentavalent Sb to trivalent Sb by antimony reductase along with decreased entry of antimony into the cell, following downregulation of the transporter, Aquaglyceroporin-1. Furthermore, as antimonials mediate their antileishmanial activity via generation of oxidative stress, upregulation of the antioxidant pathways, e.g., nonprotein thiols, protects parasites from antimony-mediated oxidative stress. Indeed, in antimony-resistant strains, the increased biosynthesis of trypanothione (a bis(glutathionyl)spermidine conjugate, T[SH]2), the major intracellular thiol of Leishmania parasites, occurs, following amplification of GSH1 gene coding for γ-glutamylcysteine synthetase and/or overexpression of ornithine decarboxylase, establishing rate-limiting steps in synthesis of glutathione and spermidine, respectively. Furthermore, an amplified T[SH]2-dependent antioxidant system, especially tryparedoxin peroxidase, also contributes by curtailing antimony-mediated production of reactive oxygen/nitrogen species. This increased formation of SbIII-thiol complexes (either spontaneously or via enzymes) if accompanied with an enhanced extrusion, at a rate sufficient to outmatch the influx, helps to sustain antimonial resistance.
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Chatterjee, M. (2013). Intracellular Mechanisms of Resistance. In: Ponte-Sucre, A., Diaz, E., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1125-3_14
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