Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei.

Author summary The uptake and metabolism of amino acids, particularly the aromatic amino acids tryptophan, phenylalanine and tyrosine, is greatly important to the survival of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Substantial differences in amino acid metabolism between parasite and human host cells provide a potential route to selective chemotherapeutic agents, which has previously been exploited in the case of the frontline HAT drug eflornithine. We have investigated analogues of the amino acid tryptophan and found that several analogues displayed selective trypanocidal potency, which strongly correlated to a structural modification of halogenation at the 7-position of the indole ring. The trypanocidal activity of these potent compounds could be reversed by supplementing growth media with excess levels of natural tryptophan, suggesting competition and direct involvement of the compounds in tryptophan metabolism. Investigation of parasite metabolism when treated with potent analogues revealed large disturbances of the parasites' metabolic function. Importantly, significant disruptions to the metabolism of aromatic amino acids were observed, giving evidence for the direct disruption of this pathway by these compounds. In the future, these analogues could serve as vital tools to gain a deeper understanding of the functional significance of these transamination processes within T. brucei parasites. Amino acid metabolism within Trypanosoma brucei, the causative agent of human African trypanosomiasis, is critical for parasite survival and virulence. Of these metabolic processes, the transamination of aromatic amino acids is one of the most important. In this study, a series of halogenated tryptophan analogues were investigated for their anti-parasitic potency. Several of these analogues showed significant trypanocidal activity. Metabolomics analysis of compound-treated parasites revealed key differences occurring within aromatic amino acid metabolism, particularly within the widely reported and essential transamination processes of this parasite.