Author: Lauren V. Carruthers, Jane C. Munday, Godwin U. Ebiloma, Pieter Steketee, Siddharth Jayaraman, Gustavo D. Campagnaro, Marzuq A. Ungogo, Leandro Lemgruber, Anne-Marie Donachie, Tim G. Rowan, Rose Peter, Liam J. Morrison, Michael P. Barrett, Harry P. De Koning
Year: 2021
About this Publication:
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 analogs DB829 and DB75. Fluorescence microscopy showed that accumulation of DB75 was inhibited by folate. Uptake of [3H]-diminazene was slow with low affinity and partly but reciprocally inhibited by folate and by competing diamidines. Expression of T. congolense folate transporters in diminazene-resistant Trypanosoma brucei 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 ?m. 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 ?m it is unclear whether this is the primary cause of the resistance.
Grant: Tryps2
Subject Areas: Research and Development
Diseases: Trypanosomosis
URL https://onlinelibrary.wiley.com/doi/10.1111/mmi.14733
Keywords:
Diminazene, Trypanosoma congolense, Trypanosome, membrane potential, mitochondria
