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

Steketee, P. C. et al. (2018) Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei. PLoS Neglected Tropical Diseases, 12(5), e0006450. (doi:10.1371/journal.pntd.0006450) (PMID:29758036) (PMCID:PMC5976210)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Achcar, Dr Fiona and MacLeod, Professor Annette and Rattigan, Dr Kevin and Giordani, Dr Federica and Barrett, Professor Michael and Vincent, Dr Isabel
Creator Roles:
Vincent, I. M.Conceptualization, Methodology, Writing – original draft, Writing – review and editing
Achcar, F.Conceptualization, Data curation, Formal analysis, Investigation, Methodology
Giordani, F.Conceptualization, Investigation, Methodology
Rattigan, K.Investigation, Methodology
MacLeod, A.Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – review and editing
Barrett, M. P.Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing – review and editing
Authors: Steketee, P. C., Vincent, I. M., Achcar, F., Giordani, F., Kim, D.-H., Creek, D. J., Freund, Y., Jacobs, R., Rattigan, K., Horn, D., Field, M. C., MacLeod, A., and Barrett, M. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN:1935-2727
ISSN (Online):1935-2735
Copyright Holders:Copyright © 2018 Steketee et al.
First Published:First published in PLoS Neglected Tropical Diseases 12(5): e0006450
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
590511Wellcome 096980/ZMichael BarrettWellcome Trust (WELLCOTR)096980/Z/11/ZIII - PARASITOLOGY
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY

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