Sodium stibogluconate (pentostam) inhibition of glucose catabolism via the glycolytic pathway, and fatty acid β-oxidation in leishmania mexicana amastigotes

Abstract

The biochemical mechanism of action of antimony (Sb) in pentavalent form complexed to gluconic acid (sodium stibogluconate)—the drug of choice for the leishmaniases—has been only slightly investigated. We recently reported that, in stibogluconate-exposed Leishmania mexicana amastigotes, there is a dose-dependent decrease in the ATP/ADP ratio [Berman et al., Antimicrob. Agents Chemother. 27, 916 (1985)]. To investigate mechanisms by which ADP phosphorylation to ATP might be inhibited, stibogluconate-exposed amastigotes were incubated with [ 14C]glucose, fatty acid, or acetate, and 14CO 2 production was determined. In organisms exposed to 500 μg Sb/ml, formation of 14CO 2 from [6- 14C] glucose and [1- 14C]palmitate was inhibited 69 and 67% respectively. In comparison, formation of 14CO 2 from [1- 14C]glucose and [2- 14C]acetate was inhibited <15%. These results suggest that glucose catabolism via glycolytic enzymes and fatty acid β-oxidation, but not glucose metabolism via the hexosemonophosphate shunt or the citric acid cycle, is specifically inhibited in stibogluconate-exposed Leishmania mexicana amastigotes. Inhibition of these pathways suggests a mechanism for the inhibition of ADP phosphorylation previously reported.