Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addit...

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Bibliographic Details
Published in:PLoS neglected tropical diseases 2018-05, Vol.12 (5), p.e0006450
Main Authors: Steketee, Pieter C, Vincent, Isabel M, Achcar, Fiona, Giordani, Federica, Kim, Dong-Hyun, Creek, Darren J, Freund, Yvonne, Jacobs, Robert, Rattigan, Kevin, Horn, David, Field, Mark C, MacLeod, Annette, Barrett, Michael P
Format: Article
Language:English
Subjects:
Acids
African trypanosomiasis
Amino acid metabolism
Antiparasitic agents
Benzoxazines - pharmacology
Biocompatibility
Bioinformatics
Biology and Life Sciences
Carnitine
Causes of
Cell cycle
Clinical trials
Dithiothreitol
Drug resistance
Drug therapy
Genomes
Health aspects
Humans
Infections
Inflammation
Lead compounds
Life sciences
Mass spectrometry
Medical research
Medicine and Health Sciences
Metabolism
Metabolites
Metabolomics
Methionine
Methyltransferase
Mode of action
Molecular chains
Oxidoreductions
Parasites
Parasitic diseases
Parasitology
Pharmacological research
Phenotypes
Physical Sciences
Physiological aspects
Protozoa
Reducing agents
Research and Analysis Methods
S-adenosylmethionine
S-Adenosylmethionine - metabolism
Scientific imaging
Side effects
Software
Tropical diseases
Trypanocidal Agents - pharmacology
Trypanosoma brucei
Trypanosoma brucei brucei - drug effects
Trypanosoma brucei brucei - genetics
Trypanosoma brucei brucei - growth & development
Trypanosoma brucei brucei - metabolism
Trypanosomiasis, African - parasitology
Vector-borne diseases
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Description
Summary:The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addition, there is emerging evidence for drug resistance. AN5568 (SCYX-7158) is a novel benzoxaborole class compound that has been selected as a lead compound for the treatment of HAT, and has demonstrated effective clearance of both early and late stage trypanosomiasis in vivo. The compound is currently awaiting phase III clinical trials and could lead to a novel oral therapeutic for the treatment of HAT. However, the mode of action of AN5568 in T. brucei is unknown. This study aimed to investigate the mode of action of AN5568 against T. brucei, using a combination of molecular and metabolomics-based approaches.Treatment of blood-stage trypanosomes with AN5568 led to significant perturbations in parasite metabolism. In particular, elevated levels of metabolites involved in the metabolism of S-adenosyl-L-methionine, an essential methyl group donor, were found. Further comparative metabolomic analyses using an S-adenosyl-L-methionine-dependent methyltransferase inhibitor, sinefungin, showed the presence of several striking metabolic phenotypes common to both treatments. Furthermore, several metabolic changes in AN5568 treated parasites resemble those invoked in cells treated with a strong reducing agent, dithiothreitol, suggesting redox imbalances could be involved in the killing mechanism.
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0006450