The potential use of inhibitors of glycerol‐3‐phosphate oxidase for chemotherapy of African trypanosomiasis

The bloodstream forms of African trypanosomes, responsible for sleeping sickness in man, are completely dependent on glycolysis for their energy supply, because the biogenesis of a mitochondrial respiratory chain is suppressed in the vertebrate host [l-4] . The present ideas on trypanosome glycolysis are presented in a simplified form in fig.1. Grant and Fulton [5] showed that the flow of carbon is consistent with the view that the Embden-Meyerhof scheme is the only pathway of glucose utilization. Pyruvate is not further metabolized because of the absence of a functional Krebs cycle [6,7] and the lack of lactate dehydrogenase [8] and is excreted into the host blood. The NAD’ reduced in the glyceraldehyde phosphate dehydrogenase step is reoxidized by a Lglycerol-3-phosphate oxidase system [9] , unique to trypanosomes (boxed in fig. 1). According to fig. 1 this oxidase system is essential for survival of bloodstream trypanosomes. Since it is absent in the mammalian host, it should provide an ideal target for a selective chemotherapeutic agent. This paper deals with the effect of salicylhydroxamic acid (SHAM), a powerful inhibitor of the glycerolphosphate oxidase system in trypanosomes, on glycolysis and on the energy production of isolated, intact trypanosomes. Although the oxidase is completely blocked by 1 mM SHAM, we have found that motility and ATP production are not drastically