The diamidine diminazene aceturate is a substrate for the high-affinity pentamidine transporter: implications for the development of high resistance levels in trypanosomes

Teka, I. A. et al. (2011) The diamidine diminazene aceturate is a substrate for the high-affinity pentamidine transporter: implications for the development of high resistance levels in trypanosomes. Molecular Pharmacology, 80(1), pp. 110-116. (doi:10.1124/mol.111.071555)

Teka, I. A. et al. (2011) The diamidine diminazene aceturate is a substrate for the high-affinity pentamidine transporter: implications for the development of high resistance levels in trypanosomes. Molecular Pharmacology, 80(1), pp. 110-116. (doi:10.1124/mol.111.071555)

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Publisher's URL: http://dx.doi.org/10.1124/mol.111.071555

Abstract

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 K-m 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Munday, Dr Jane and De Koning, Professor Harry and Matovu, Dr Enock and Barrett, Professor Michael
Authors: Teka, I. A., Kazibwe, A. J. N., El-Sabbagh, N., Al-Salabi, M. I., Ward, C. P., Eze, A. A., Munday, J. C., Maser, P., Matovu, E., Barrett, M. P., and De Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Molecular Pharmacology
Journal Abbr.:Mol. Pharmacol.
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0026-895X
ISSN (Online):1521-0111
Published Online:24 March 2011
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
471291Drug resistance in African trypanosomesHarry De KoningMedical Research Council (MRC)G0701258Infection Immunity and Inflammation Life Sciences