Chemotherapy of human
African trypanosomiasis (HAT) is unsatisfactory because only a few drugs, with serious side effects and poor efficacy, are available. As
drug combination regimes often achieve greater therapeutic efficacy than monotherapies, here the trypanocidal activity of the
cysteine protease inhibitor K11777 in combination with current anti-HAT drugs using bloodstream forms of Trypanosoma brucei was investigated. Isobolographic analysis was used to determine the interaction between
cysteine protease inhibitors (
K11777, CA-074Me and
CAA0225) and anti-HAT drugs (
suramin,
pentamidine,
melarsoprol and
eflornithine). Bloodstream forms of T. brucei were incubated in culture medium containing
cysteine protease inhibitors or anti-HAT drugs alone or in combination at a 1:1 fixed-dose ratio. After 48 h incubation, live cells were counted, the 50% growth inhibition values determined and combination indices calculated. The general cytotoxicity of
drug combinations was evaluated with human leukaemia HL-60 cells. Combinations of
K11777 with
suramin,
pentamidine and
melarsoprol showed antagonistic effects while with
eflornithine a synergistic effect was observed. Whereas
eflornithine antagonises with
CA-074Me, an inhibitor inactivating the targeted TbCATL only under reducing conditions, it synergises with CAA0255, an inhibitor structurally related to
CA-074Me which inactivates TbCATL independently of
thiols. These findings indicate an essential role of
thiols for the synergistic interaction between
K11777 and
eflornithine. Encouragingly, the
K11777/
eflornithine combination displayed higher trypanocidal than cytotoxic activity. The results of this study suggest that the combination of the
cysteine protease inhibitor K11777 and
eflornithine display promising synergistic trypanocidal activity that warrants further investigation of the
drug combination as possible alternative treatment of HAT.