Inhibitors of the trypanosome alternative oxidase reduce parasite growth in culture

Abstract

African trypanosomiasis is a deadly disease for which few chemotherapeutic options are available. The causative agents, Trypanosoma brucei rhodesiense and T. b. gambiense, use a non-cytochrome alternative oxidase for respiration. The absence of this enzyme in mammals makes it a logical therapeutic target. We designed three compounds, ACB41, ACD15, and ACD16, and tested them for their ability to inhibit activity of the trypanosome alternative oxidase (TAO). All three compounds contain a central benzene ring substituted with a hydroxyl group, analogous to that present in SHAM, and a prenyl chain similar to that found in ubiquinol. ACD15 and ACD16 are further differentiated by the presence of a solubility-enhancing carbohydrate moiety. Kinetic studies with purified TAO show that all three compounds competitively inhibit TAO, and two compounds, ACB41 and ACD15, have inhibition constants 6- and 3-fold more potent than SHAM, respectively. Studies of the respiration activity of trypanosomes indicate that all the compounds inhibit respiration of the bloodstream form, while respiration of the procyclic form is largely unaffected. All the compounds inhibited the growth of continuously cultured bloodstream trypanosomes, and two compounds, ACB41 and ACD15, killed bloodstream trypanosomes incubated for short periods at higher concentrations. Results suggest we have identified compounds that have trypanocidal properties in vitro and merit further investigation.