Inhibition of glutathione synthesis as a chemotherapeutic strategy for leishmaniasis

Abstract

SummaryThis study focuses on the use of buthionine sulphoximine (BSO), a ␥-glutamylcysteine synthetase inhibitor, on Leishmania donovani growth. The effect of BSO on amastigote multiplication within macrophages showed that 5 mm BSO decreased infectivity by about 50% and the mean number of amastigotes per 100 infected macrophages by 21%. The mechanism may be that BSO resulted in enhanced nitric oxide (NO) levels within macrophages, probably due to inhibition of GSH content since GSH (10 mM) given after BSO treatment led to a decrease in NO compared to macrophages treated with BSO alone which were preexposed to the Leishmania surface molecule lipophosphoglycan.keywords glutathione, l-buthionine sulphoximine (BSO), Leishmania donovani, nitric oxide correspondence Dr R. Madhubala,

Buthionine Sulfoximine Increases the Toxicity of Nifurtimox and Benznidazole to Trypanosoma cruzi

“…Similar approaches with an in vitro model with megazol in T. brucei (11) and with Leishmania (17) have been reported. Nevertheless, in the Leishmania model BSO was barely effective (17).…”

Leishmania amazonensis trypanothione reductase: Evaluation of the effect of glutathione analogs on parasite growth, infectivity and enzyme activity

“…Studies related to GSS and TS inhibitors, using glutathione analogs, showed that the substitution of the L-Cys in glutathione by hydrophobic amino acids, as L-leu and L-val, result in efficient non-competitive inhibitors of these enzymes. However, overall, these inhibitors did not appear to be efficient against Leishmania sp., probably due to the action of proteases and to the difficulty of the compounds to penetrate through cellular membrane [19,20]. Taking these inhibitors as prototypes, two series of tripeptids were synthesized; in one series, beside the change of aminoacids, benzyl esther radicals were included on C and N terminal groups of the glutamic acid (ASC-I-74A, ASC-I-75A, ASC-I-74B and ASC-I-75B), which increase the lipophilicity of the molecule.…”

The In Vivo Susceptibility of Leishmania donovani to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis

“…This result perhaps indicates a stability problem with BSO, although it was stored as recommended by the manufacturer. BSO has already been shown to have antileishmanial properties, since in vitro treatment of L. donovani-infected macrophages with 5 mM BSO reduced the percentage of cells infected and the mean number of parasites per cell (17).…”