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)
|
Text
162932.pdf - Published Version Available under License Creative Commons Attribution. 10MB |
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: | Rattigan, Dr Kevin and Vincent, Dr Isabel and Achcar, Dr Fiona and MacLeod, Professor Annette and Giordani, Dr Federica and Barrett, Professor Michael |
| 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 > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| 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
Funder and Project Information
Funder and Project Information