Diminazene resistance in Trypanosoma congolense is not caused by reduced transport capacity but associated with reduced mitochondrial membrane potential

Carruthers, L. V. et al. (2021) Diminazene resistance in Trypanosoma congolense is not caused by reduced transport capacity but associated with reduced mitochondrial membrane potential. Molecular Microbiology, 116(2), pp. 564-588. (doi: 10.1111/mmi.14733) (PMID:33932053)

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Trypanosoma congolense is a principal agent causing livestock trypanosomiasis in Africa, costing developing economies billions of dollars and undermining food security. Only the diamidine diminazene and the phenanthridine isometamidium are regularly used, and resistance is widespread but poorly understood. We induced stable diminazene resistance in T. congolense strain IL3000 in vitro. There was no cross‐resistance with the phenanthridine drugs, melaminophenyl arsenicals, oxaborole trypanocides, or with diamidine trypanocides, except the close analogues DB829 and DB75. Fluorescence microscopy showed that accumulation of DB75 was inhibited by folate. Uptake of [3H]‐diminazene was slow, low affinity and partly but reciprocally inhibited by folate and by competing diamidines. Expression of T. congolense folate transporters in diminazene‐resistant T. b. brucei significantly sensitized the cells to diminazene and DB829, but not to oxaborole AN7973. However, [3H]‐diminazene transport studies, whole genome sequencing and RNA‐seq found no major changes in diminazene uptake, folate transporter sequence or expression. Instead, all resistant clones displayed a moderate reduction in the mitochondrial membrane potential. We conclude that diminazene uptake in T. congolense proceed via multiple low affinity mechanisms including folate transporters; while resistance is associated with a reduction in Ψm it is unclear whether this is the primary cause of the resistance.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Carruthers, Dr Lauren and Ebiloma, Mr Godwin and Munday, Dr Jane and Ungogo, Mr Marzuq and Campagnaro, Gustavo and De Koning, Professor Harry and Lemgruber Soares, Dr Leandro and Donachie, Ms Anne Marie and Morrison, Dr Liam and Barrett, Professor Michael
Authors: Carruthers, L. V., Munday, J. C., Ebiloma, G. U., Steketee, P., Jayaraman, S., Campagnaro, G. D., Ungogo, M., Lemgruber, L., Donachie, A.-M., Rowan, T. G., Peter, R., Morrison, L. J., Barrett, M. P., and De Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Molecular Microbiology
ISSN (Online):1365-2958
Published Online:01 May 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Molecular Microbiology 116(2): 564-588
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172474A new drug discovery pipeline for animal African trypanosomiasisMichael BarrettBiotechnology and Biological Sciences Research Council (BBSRC)BB/N007999/1III - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology