Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness

The drugs in clinical use against African sleeping sickness are toxic, cost ly, or inefficient. We show that Trypanosoma brucei, which causes this dise ase, has very low levels of CTP, which are due to a limited capacity for de novo synthesis and the lack of salvage pathways. The CTP synthetase inhibi tors 6-diazo-5-oxo-L-norleucine (DON) and alpha -amino-3-chloro-4,5-dihydro -5-isoxazoleacetic acid (acivicin) reduced the parasite CTP levels even fur ther and inhibited trypanosome proliferation in vitro and in T. brucei-infe cted mice. In mammalian cells, DON mainly inhibits de novo purine biosynthe sis, a pathway lacking in trypanosomes. We could rescue DON-treated human a nd mouse fibroblasts by the addition of the purine base hypoxanthine to the growth medium. For treatment of sleeping sickness, we propose the use of C TP synthetase inhibitors alone or in combination with appropriate nucleosid es or bases.