Introduced about a century ago, suramin remains a frontline drug for the management of early-stage East African trypanosomiasis (sleeping sickness). Cellular entry into the causative agent, the protozoan parasite Trypanosoma brucei, occurs through receptor-mediated endocytosis involving the parasite's invariant surface glycoprotein 75 (ISG75), followed by transport into the cytosol via a lysosomal transporter. The molecular basis of the trypanocidal activity of suramin remains unclear, but some evidence suggests broad, but specific, impacts on trypanosome metabolism (i.e. polypharmacology). Here we observed that suramin is rapidly accumulated in trypanosome cells proportionally to ISG75 abundance. Although we found little evidence that suramin disrupts glycolytic or glycosomal pathways, we noted increased mitochondrial ATP production, but a net decrease in cellular ATP levels. Metabolomics highlighted additional impacts on mitochondrial metabolism, including partial Krebs' cycle activation and significant accumulation of pyruvate, corroborated by increased expression of mitochondrial enzymes and transporters. Significantly, the vast majority of suramin-induced proteins were normally more abundant in the insect forms compared with the blood stage of the parasite, including several proteins associated with differentiation. We conclude that suramin has multiple and complex effects on trypanosomes, but unexpectedly partially activates mitochondrial ATP-generating activity. We propose that despite apparent compensatory mechanisms in drug-challenged cells, the suramin-induced collapse of cellular ATP ultimately leads to trypanosome cell death.

Department of Biological and Medical Sciences Oxford Brookes University Oxford United Kingdom

Department of Pathology University of Cambridge Cambridge United Kingdom

Institute for Infection Immunity and Inflammation College of Medical Veterinary and Life Sciences University of Glasgow Glasgow United Kingdom

Institute of Parasitology Biology Centre Czech Academy of Sciences Institute of Parasitology Faculty of Science University of South Bohemia České Budějovice Czech Republic

School of Life Sciences University of Dundee Dundee Scotland United Kingdom

School of Life Sciences University of Dundee Dundee Scotland United Kingdom Institute of Parasitology Biology Centre Czech Academy of Sciences Institute of Parasitology Faculty of Science University of South Bohemia České Budějovice Czech Republic

School of Life Sciences University of Nottingham Nottingham United Kingdom

Wellcome Centre for Integrative Parasitology and Glasgow Polyomics University of Glasgow Glasgow United Kingdom

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