Drugs and Transporters in Kinetoplastid Protozoa

Landfear, Scott M.

doi:10.1007/978-0-387-77570-8_3

Cited by 26 publications

(2 citation statements)

References 58 publications

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“…In T. brucei , resistance to DA is linked to loss of the TbAT1/P2 transporter [6,11,25]. While T. congolense does not have an equivalent transporter [44], drug resistance in trypanosomatids has very often been associated with the loss of transporters at the plasma membrane [10,12,45] and we thus investigated whether uptake of [ 3 H]-DA was altered in the resistant clones.…”

Section: Resultsmentioning

confidence: 99%

Diminazene resistance inTrypanosoma congolenseis linked to reduced mitochondrial membrane potential and not to reduced transport capacity

Carruthers

Munday

Ebiloma

et al. 2020

Preprint

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Trypanosoma congolense is one of the principal agents causing livestock trypanosomiasis in sub-Saharan Africa. This wasting disease is costing these developing economies billions of dollars and undermining food security. Only two old drugs, the diamidine diminazene and the phenanthridine isometamidium are regularly used, and resistance is widespread but poorly understood. We induce diminazene resistance in T. congolense laboratory strain IL3000 in vitro. Resistance was stable and not deleterious to in vitro growth. There was no cross-resistance with the phenanthridine drugs, with melaminophenyl arsenicals, with two promising new oxaborole trypanocides, nor with other diamidine trypanocides such as pentamidine, except the close structural analogues DB829 and DB75. Fluorescence microscopy showed that accumulation of DB75 was inhibited by folate. Uptake of [3H]-diminazene was also partly inhibited by folate, as well as by competing diamidine drugs, albeit at quite high concentrations, and uptake of tritiated diminazene and pentamidine was slow and low affinity. Uptake of [3H]-folate was in turn partly inhibited by diminazene, and inhibition of diminazene uptake by folate and pentamidine appeared to be additive, indicating multiple low affinity transport mechanisms for the drug. Expression of the T. congolense folate transporters TcoFT1-3 in diminazene-resistant T. b. brucei significantly sensitized the cells to diminazene and DB829, but not to oxaborole AN7973. However, [3H]-diminazene uptake was not different in T. congolense IL3000 and its diminazene resistant clones and RNAseq and whole-genome sequencing of multiple resistant clones did not reveal major changes in folate transporter sequence or expression. Instead, flow cytometry revealed a strong and stable reduction in the mitochondrial membrane potential Ψm in all resistant clones. We conclude that diminazene uptake in T. congolense proceed via multiple low affinity mechanisms including folate transporters and that resistance is the result of a reduction in Ψm that limits mitochondrial accumulation of the drug.

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Section: Resultsmentioning

confidence: 99%

Diminazene resistance inTrypanosoma congolenseis linked to reduced mitochondrial membrane potential and not to reduced transport capacity

Carruthers

Munday

Ebiloma

et al. 2020

Preprint

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“…Equilibrative Nucleoside Transporters (ENTs) and Concentrative Nucleoside Transporters (CNTs) working as permeases (Young et al 2008). The ENTs differ from CNTs in the context that they do not concentrate their substrates but simply mediate flux down a thermodynamic gradient (Landfear 2008). However, ENT family members from L. donovani are reported as electrogenic proton symporters (Stein et al 2003), but this does not confirm their role as concentrative transporters.…”

Section: Extracellular Nucleoside/nucleobase Transportermentioning

confidence: 99%

Dependence of Leishmania parasite on host derived ATP: an overview of extracellular nucleotide metabolism in parasite

Arora

Kumar

2018

J Parasit Dis

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The widespread role of ATP in humans has been characterized as a substrate for metabolism as well as other key processes occurring in the human system. Hence, the ATP pool may also be accessible to the invaders, including Leishmania donovani (a protozoan parasite), considering the fact that ATP is not scarce at the cellular location where the pathogen resides. The protozoan parasite survives in the human host by utilizing purines from its extracellular environment, due to its inability to synthesize purines de novo. The purines are accessible in the form of nucleoside triphosphates (NTPs), for example, adenosine (ADO) in the form of ATP molecules. These NTPs are processed by the ecto-nucleotidases in the transmembrane region of the parasite, which are then transported inside via nucleoside/ nucleobase transporters belonging to the ENT family of & Ambak Kumar Rai

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Glucose Transporters in Parasitic Protozoa

Landfear

2010

Methods in Molecular Biology

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Glucose and related hexoses play central roles in the biochemistry and metabolism of single cell parasites such as Leishmania, Trypanosoma, and Plasmodium that are the causative agents of leishmaniasis, African sleeping sickness, and malaria. Glucose transporters and the genes that encode them have been identified in each of these parasites and their functional properties have been scrutinized. These transporters are related in sequence and structure to mammalian facilitative glucose transporters of the SLC2 family, but they are nonetheless quite divergent in sequence. Hexose transporters have been shown to be essential for the viability of the infectious stage of each of these parasites and thus may represent targets for development of novel anti-parasitic drugs. The study of these transporters also illuminates many aspects of the basic biology of Leishmania, trypanosomes, and malaria parasites.

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Drugs and Transporters in Kinetoplastid Protozoa

Cited by 26 publications

References 58 publications

Diminazene resistance inTrypanosoma congolenseis linked to reduced mitochondrial membrane potential and not to reduced transport capacity

Diminazene resistance inTrypanosoma congolenseis linked to reduced mitochondrial membrane potential and not to reduced transport capacity

Dependence of Leishmania parasite on host derived ATP: an overview of extracellular nucleotide metabolism in parasite

Glucose Transporters in Parasitic Protozoa

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