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

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.

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


Pieter C. Steketee

Isabel M. Vincent

Fiona Achcar

Federica Giordani

Darren J. Creek

Yvonne Freund

Robert Jacobs

Kevin Rattigan

David Horn

Mark C. Field

Annette MacLeod

Michael P. Barrett


Timothy G. Geary


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.


Steketee, P. C., Vincent, I. M., Achcar, F., Giordani, F., Kim, D., Creek, D. J., …Barrett, M. P. (2018). Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei. PLoS Neglected Tropical Diseases, 12(5), Article e0006450.

Journal Article Type Article
Acceptance Date Apr 15, 2018
Online Publication Date May 14, 2018
Publication Date May 14, 2018
Deposit Date Jan 11, 2019
Publicly Available Date Jan 11, 2019
Journal PLOS Neglected Tropical Diseases
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 12
Issue 5
Article Number e0006450
Keywords Public Health, Environmental and Occupational Health; Infectious Diseases
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