Inhibition of succinyl CoA synthetase histidine-phosphorylation in Trypanosoma brucei by an inhibitor of bacterial two-component systems.

Recent drug screenings for new antibacterial drugs directed against histidine phospho-relay signalling pathways in bacteria have resulted in compounds which potently inhibit the histidine kinase activity of bacterial two-component systems. The present study demonstrates that one of these compounds, LY266500, is also a potent inhibitor of histidine phosphorylation in the unicellular eukaryotic parasite Trypanosoma brucei, both in vitro and in whole cells. In vitro, it inhibits histidine phosphorylation of mitochondrial succinyl CoA synthetase. LY26650 does not interfere with the phosphotransfer from the histidine-phosphorylated protein to ADP. In standardized cell culture tests, LY266500 potently inhibits the proliferation of the human pathogens T. brucei rhodesiense and Leishmania donovani. Since the inhibitory activity in vivo is life-cycle stage specific and correlates well with the mitochondrial activity in the different stages, the effect of LY266500 is most likely due to its specific inhibition of the mitochondrial succinyl CoA synthetase.