RT Journal Article
SR Electronic
T1 The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 110
OP 116
DO 10.1124/mol.111.071555
VO 80
IS 1
A1 Ibrahim A. Teka
A1 Anne J. N. Kazibwe
A1 Nasser El-Sabbagh
A1 Mohammed I. Al-Salabi
A1 Christopher P. Ward
A1 Anthonius A. Eze
A1 Jane C. Munday
A1 Pascal Mäser
A1 Enock Matovu
A1 Michael P. Barrett
A1 Harry P. de Koning
YR 2011
UL http://molpharm.aspetjournals.org/content/80/1/110.abstract
AB African trypanosomiasis is a disease of humans and livestock in many areas south of the Sahara. Resistance to the few existing drugs is a major impediment to the control of these diseases, and we investigated how resistance to the main veterinary drug diminazene aceturate correlates with changes in drug transport in resistant strains. The strain tbat1(−/−), lacking the TbAT1/P2 aminopurine transporter implicated previously in diminazene transport, was adapted to higher levels of diminazene resistance. The resulting cell line was designated ABR and was highly cross-resistant to other diamidines and moderately resistant to cymelarsan. Procyclic trypanosomes were shown to be a convenient model to study diamidine uptake in Trypanosoma brucei brucei given the lack of TbAT1/P2 and a 10-fold higher activity of the high-affinity pentamidine transporter (HAPT1). Diminazene could be transported by HAPT1 in procyclic trypanosomes. This drug transport activity was lacking in the ABR line, as reported previously for the pentamidine-adapted line B48. The Km for diminazene transport in bloodstream tbat1(−/−) trypanosomes was consistent with uptake by HAPT1. Diminazene transport in ABR and B48 cells was reduced compared with tbat1(−/−), but their resistance phenotype was different: B48 displayed higher levels of resistance to pentamidine and the melaminophenyl arsenicals, whereas ABR displayed higher resistance to diminazene. These results establish a loss of HAPT1 function as a contributing factor to diminazene resistance but equally demonstrate for the first time that adaptations other than those determining the initial rates of drug uptake contribute to diamidine and arsenical resistance in African trypanosomes.