Molecular and biochemical approaches of the trypanothione system in Leishmania spp.: A key player in parasite resistance to antimonial therapy

Abstract

The trypanothione system is a crucial antioxidant defense mechanism in Leishmania spp. The enzymes involved, including trypanothione reductase (TR), trypanothione synthetase (TS), tryparedoxin (TXN) and tryparedoxin peroxidase (TXNPx) are essential for maintaining the redox balance. This system plays a fundamental role in the biology of Leishmania spp., contributing to parasite resistance against metalloid-based treatments, such as trivalent antimony (Sb³⁺). The mechanisms underlying this resistance, particularly those linked to the functionality of the trypanothione system, have garnered increasing interest. This review prioritizes studies conducted with clinical isolates of Leishmania spp. that evaluated gene expression, protein abundance, and enzyme activity to determine how variations in trypanothione-related mechanisms influence their clinical outcomes. Additionally, complementary strategy involving different protocols to determine intracellular non-protein thiols have further enrich the information into these studies. Notably, the evidence gathered here highlights that studies have focused on only four Leishmania spp. with just one belonging to the Viannia subgenus. Several approaches have been used to determine TR and TXNPx enzyme activity in parasite lysates, supporting their use as tools for studying resistant phenotypes. Additionally, the assessment of TR, TXNPx and TS activities has been applied in kinetic studies for screening of inhibitor compounds. The functional insights presented herein may aid in elucidating the basis of parasite resistance and guide the development of more effective therapeutic strategies against leishmaniasis in its different clinical forms.