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MeSH: trypanozomóza africká-farmakoterapie

10 záznamů v Medvik Filtry

Článek

Suramin action in African trypanosomes involves a RuvB-like DNA helicase

Albisetti, Anna
Autor Albisetti, Anna Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland University of Basel, Petersplatz 1, 4001, Basel, Switzerland
Hälg, Silvan
Autor Hälg, Silvan Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland University of Basel, Petersplatz 1, 4001, Basel, Switzerland
Zoltner, Martin
Autor Zoltner, Martin Department of Parasitology, Faculty of Science, Charles University in Prague, Biocev, Vestec, Czech Republic
Mäser, Pascal
Autor Mäser, Pascal Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland University of Basel, Petersplatz 1, 4001, Basel, Switzerland
Wiedemar, Natalie
Autor Wiedemar, Natalie Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland University of Basel, Petersplatz 1, 4001, Basel, Switzerland. Electronic address: natalie.wiedemar@unibe.ch

International journal for parasitology. Drugs and drug resistance. 2023 ; 23 (-) : 44-53. [pub] 20230919

Int J Parasitol Drugs Drug Resist
ISSN 2211-3207
Medvik
Zdroj

Suramin is one of the oldest drugs in use today. It is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense, and it is also used for surra in camels caused by Trypanosoma evansi. Yet despite one hundred years of use, suramin's mode of action is not fully understood. Suramin is a polypharmacological molecule that inhibits diverse proteins. Here we demonstrate that a DNA helicase of the pontin/ruvB-like 1 family, termed T. brucei RuvBL1, is involved in suramin resistance in African trypanosomes. Bloodstream-form T. b. rhodesiense under long-term selection for suramin resistance acquired a homozygous point mutation, isoleucine-312 to valine, close to the ATP binding site of T. brucei RuvBL1. The introduction of this missense mutation, by reverse genetics, into drug-sensitive trypanosomes significantly decreased their sensitivity to suramin. Intriguingly, the corresponding residue of T. evansi RuvBL1 was found mutated in a suramin-resistant field isolate, in that case to a leucine. RuvBL1 (Tb927.4.1270) is predicted to build a heterohexameric complex with RuvBL2 (Tb927.4.2000). RNAi-mediated silencing of gene expression of either T. brucei RuvBL1 or RuvBL2 caused cell death within 72 h. At 36 h after induction of RNAi, bloodstream-form trypanosomes exhibited a cytokinesis defect resulting in the accumulation of cells with two nuclei and two or more kinetoplasts. Taken together, these data indicate that RuvBL1 DNA helicase is involved in suramin action in African trypanosomes.

MeSH
DNA-helikasy genetika MeSH
suramin farmakologie terapeutické užití MeSH
Trypanosoma brucei brucei * genetika MeSH
Trypanosoma brucei rhodesiense genetika MeSH
Trypanosoma * genetika MeSH
trypanozomóza africká * farmakoterapie MeSH
zvířata MeSH
Check Tag
zvířata MeSH
Publikační typ
časopisecké články MeSH

Článek

Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline

PLOS pathogens. 2021 ; 17 (3) : e1009204. [pub] 20210301

PLoS Pathog
ISSN 1553-7374
Medvik
Zdroj

Trypanosoma brucei, a protist responsible for human African trypanosomiasis (sleeping sickness), is transmitted by the tsetse fly where the procyclic forms of the parasite develop in the proline-rich (1-2 mM) and glucose-depleted digestive tract. Proline is essential for the midgut colonization of the parasite in the insect vector, however other carbon sources could be available and used to feed its central metabolism. Here we show that procyclic trypanosomes can consume and metabolize metabolic intermediates, including those excreted from glucose catabolism (succinate, alanine and pyruvate), with the exception of acetate, which is the ultimate end-product excreted by the parasite. Among the tested metabolites, tricarboxylic acid (TCA) cycle intermediates (succinate, malate and α-ketoglutarate) stimulated growth of the parasite in the presence of 2 mM proline. The pathways used for their metabolism were mapped by proton-NMR metabolic profiling and phenotypic analyses of thirteen RNAi and/or null mutants affecting central carbon metabolism. We showed that (i) malate is converted to succinate by both the reducing and oxidative branches of the TCA cycle, which demonstrates that procyclic trypanosomes can use the full TCA cycle, (ii) the enormous rate of α-ketoglutarate consumption (15-times higher than glucose) is possible thanks to the balanced production and consumption of NADH at the substrate level and (iii) α-ketoglutarate is toxic for trypanosomes if not appropriately metabolized as observed for an α-ketoglutarate dehydrogenase null mutant. In addition, epimastigotes produced from procyclics upon overexpression of RBP6 showed a growth defect in the presence of 2 mM proline, which is rescued by α-ketoglutarate, suggesting that physiological amounts of proline are not sufficient per se for the development of trypanosomes in the fly. In conclusion, these data show that trypanosomes can metabolize multiple metabolites, in addition to proline, which allows them to confront challenging environments in the fly.

MeSH
citrátový cyklus účinky léků MeSH
glukosa metabolismus MeSH
hmyz - vektory parazitologie MeSH
moucha tse-tse účinky léků parazitologie MeSH
oxidace-redukce účinky léků MeSH
prolin metabolismus farmakologie MeSH
RNA interference fyziologie MeSH
Trypanosoma brucei brucei účinky léků metabolismus MeSH
Trypanosoma účinky léků metabolismus MeSH
trypanozomóza africká farmakoterapie MeSH
zvířata MeSH
Check Tag
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs

PLOS pathogens. 2020 ; 16 (11) : e1008932. [pub] 20201103

PLoS Pathog
ISSN 1553-7374
Medvik
Zdroj

Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.

Článek

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

eLife. 2020 ; 9 (-) : . [pub] 20200811

ISSN 2050-084X
Medvik
Zdroj

Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.