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Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals. It has been speculated that resistance may be the result of reduced diminazene uptake by the parasite. We describe here the mechanisms by which (3)Hdiminazene is transported by Trypanosoma brucei brucei bloodstream forms. Diminazene was rapidly accumulated through a single transporter, with a K(m) of 0.45 +/- 0.11 micro M, which was dose dependently inhibited by pentamidine and adenosine. The K(i) values for these inhibitors were consistent with this transporter being the P2/TbAT1 adenosine transporter. Yeast expressing TbAT1 acquired the ability to take up (3)Hdiminazene and (3)Hpentamidine. TbAT1-null mutants had lost almost all capacity for (3)Hdiminazene transport. However, this cell line still displayed a small but detectable rate of (3)Hdiminazene accumulation, in a nonsaturable manner. We conclude that TbAT1 mediates (3)Hdiminazene transport almost exclusively and that this explains the observed diminazene resistance phenotypes of TbAT1-null mutants and field isolates.
Koning et al. (Thu,) studied this question.