RT Journal Article
SR 00
ID 10.1371/journal.pntd.0006450
A1 Steketee, Pieter C.
A1 Vincent, Isabel M.
A1 Achcar, Fiona
A1 Giordani, Federica
A1 Kim, Dong-Hyun
A1 Creek, Darren J.
A1 Freund, Yvonne
A1 Jacobs, Robert
A1 Rattigan, Kevin
A1 Horn, David
A1 Field, Mark C.
A1 MacLeod, Annette
A1 Barrett, Michael P.
T1 Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei
JF PLoS Neglected Tropical Diseases
YR 2018
FD 2018-05-14
VO 12
IS 5
AB 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.
PB Public Library of Science
SN 1935-2727
LK https://eprints.gla.ac.uk/162932/