Disrupting Leishmania redox homeostasis: Mechanistic insights into a platinum-based antileishmanial complex

AbstractLeishmaniasis remains a major neglected tropical disease, and the development of new chemotherapeutic agents with improved selectivity and novel mechanisms is urgently required. Since the discovery of cisplatin, platinum-based compounds have been extensively developed for cancer therapy; however, their potential in the treatment of parasitic infections has received limited attention. Here, we report a mechanistic investigation of the antileishmanial activity of the platinum(II) complex [PtCl(phpy)(PTA)], incorporating the oxidation-resistant phosphine ligand 1,3,5-triaza-7-phosphaadamantane. The complex exhibited low-micromolar activity against Leishmania (L.) amazonensis promastigotes and axenic amastigotes, with a favorable selectivity index relative to mammalian cells. Biological and biochemical analyses demonstrated that [PtCl(phpy)(PTA)] disrupts parasite mitochondrial bioenergetics, leading to impaired respiration, loss of mitochondrial membrane potential, and oxidative imbalance. In addition, the complex inhibited trypanothione reductase activity, a key enzyme in parasite redox homeostasis. This inhibition was accompanied by increased NADPH production via the pentose phosphate pathway, indicating a compensatory response to redox stress. Overall, these findings underscore the potential of platinum-based complexes to target redox and mitochondrial pathways in Leishmania, supporting metal-mediated redox disruption as a promising strategy for antileishmanial drug development.