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.
Highlights
We study the effects of AN5568 on intracellular metabolism of the parasite and show changes to pathways involved in S-adenosyl-methionine metabolism
The monoflagellate protozoan parasite Trypanosoma brucei is the causative agent of Human African trypanosomiasis (HAT), and is one of three species that cause Nagana in livestock [1]
Efficacy of AN5568 was determined in both bloodstream form (BSF) and procyclic form (PCF) parasites of the Lister 427 strain, by calculating the half maximal effective concentration (EC50) (Table 1)
Summary
The monoflagellate protozoan parasite Trypanosoma brucei is the causative agent of Human African trypanosomiasis (HAT), and is one of three species that cause Nagana in livestock [1]. HAT is prevalent in sub-Saharan Africa and is responsible for a significant socio-economic burden. Gambiense, in West Africa, with the remaining cases attributed to T. b. Cases have decreased in recent years from 38,000 in 1998 to fewer than 3,000 in 2015 [3], leading to the gambiense form of the disease being targeted by the WHO for elimination [4]. Current therapeutics against HAT are inadequate, and in some cases, highly toxic, leading to fatal side effects—including a reactive encephalopathy in significant numbers of patient treated with melarsoprol [6]. There is evidence of resistance to these drugs in the field [7] and current therapeutics frequently target only one T. brucei subspecies, or either early- or latestage HAT [8]. There is a desperate need for novel and improved therapeutics to combat HAT
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