Biochemical mechanisms of the antileishmanial activity of sodium stibogluconate

Abstract

Pentavalent antimonial agents such as sodium stibogluconate (Pentostam; Burroughs Welicome Co., London, United Kingdom) are the drugs of choice for the treatment of leishmaniasis, but their biochemical mechanisms of action are virtually unknown. The viability of Leishmania mexicana (WR 227) promastigotes and amastigotes was decreased 40 to 61% by a 4-h exposure to 500 ji.g of Sb (in the form of stibogluconate) per ml. Such exposure also resulted in a 51 to 65% decrease in incorporation of label into DNA, RNA, and protein; a 56 to 65% decrease in incorporation of label into purine nucleoside triphosphate; and a 34 to 60% increase in incorporation of label into purine nucleoside monophosphate and diphosphate. It is postulated that the apparent decrease in ATP and GTP synthesis from ADP and GDP contributes to decreased macromolecular synthesis and to decreased Leishmania viability. Further experiments suggested that inhibition of glycolysis and the citric acid cycle may partially explain the inability to phosphorylate ADP.Leishmaniasis is initiated when sand flies inject the extracellular promastigote form of the parasite into the skin. Promastigotes are rapidly phagocytized, after which they transform into the intracellular amastigote form. Promastigotes are not seen in clinical lesions; the multiplication of amastigotes within macrophages leads to clinical disease.Pentavalent antimonial agents in the form of sodium stibogluconate (Pentostam; Burroughs Wellcome Co., London, United Kingdom) or meglumine antimonate (Glucantime; Specia, Paris, France) are the primary therapeutic agents for all forms of leishmaniasis (1, 10). Although some form of antimony may have been in use for leishmaniasis since the days of the ancient Greeks (16) and the present formulations were developed in the 1940s, the biochemical mechanisms of the antileishmanial activity of antimony are virtually uninvestigated.Until recently, trivalent antimonial agents were used clinically for schistosomiasis. Bueding and Mansour found that 10-4 to 1O-3 M (approximately 30 to 300 ,ug/ml) potassium antimony tartrate inhibited Schistosoma mansoni survival and schistosomal phosphofructokinase activity by 50% but poorly inhibited mammalian phosphofructokinase (3,11). Since the product of the phosphofructokinase reaction is the substrate for aldolase and aldolase is the rate-limiting enzyme in S. mansoni glycolysis, the authors reasoned that the mechanisms by which trivalent Sb inhibited schistosomal glycolysis had been elucidated. They also hypothesized that such inhibition of glycolysis might be the mechanism for the antischistosomal activity of the drug and for the greater toxicity of Sb to schistosoma than to mammalian cells.We are not aware of a systematic evaluation of the effect of antimonial agents on leishmanial energy metabolism or on other leishmanial biochemical pathways. We report here the effect of antileishmanial concentrations of stibogluconate on macromolecular synthesis, purine nucleotide synthesis, and energy metabolism of Leishmania mexic...

Antimonial-induced Increase in Intracellular Ca2+ through Non-selective Cation Channels in the Host and the Parasite Is Responsible for Apoptosis of Intracellular Leishmania donovani Amastigotes

“…The actual survival of intracellular amastigotes encountered in the mammalian host determines disease pathogenesis. Importantly, promastigote and amastigote forms surviving in two disparate biological environments are very different in terms of metabolic pathways and their susceptibility to anti-leishmanial compounds (13,14). Therefore, observations with intracellular amastigotes addressing questions related to parasite survival are more relevant and could lay the foundation for rational strategies of drug development.…”

Expresión diferencial de proteínas en Leishmania (Viannia) panamensis asociadas con mecanismos de resistencia a antimoniato de meglumina

“…Se utilizaron concentraciones crecientes y graduales de antimonio (8,12,16,20,24,26,28,32, 33 mg/ml), hasta alcanzar una concentración final de 37 mg/ml. En un trabajo previo, para demostrar un comportamiento diferencial frente al medicamento entre la cepa susceptible y la resistente al antimonio pentavalente, se evaluó la resistencia in vivo infectando hámsters con las dos cepas y midiendo el tamaño de la nariz antes de la inoculación, después del desarrollo de la lesión (día 42), terminado el tratamiento con antimonio pentavalente (día 52) y cinco días después del tratamiento (día 57) (no se presentan los datos).…”

“…Se han reportado varios blancos celulares para el antimonio pentavalente y el antimonio trivalente , incluyendo el tripanotión, que es el principal agente reductor de tioles en el parásito (20)(21)(22).…”

Drug Resistance in Leishmaniasis

“…Initial studies suggested that sodium stibogluconate [Sb(V)] inhibits macromolecular biosynthesis in amastigotes (18), possibly via perturbation of energy metabolism due to inhibition of glycolysis and fatty acid ␤-oxidation (16). However, the specific targets in these pathways have not been identified.…”