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.

• Klíčová slova
• Trypanosoma brucei, differentiation, drug action, drug mechanisms, energy homeostasis, glycosomes, metabolomics, parasite metabolism, polypharmacology, proteomics, sleeping sickness, suramin, trypanosome,
• MeSH
• adenosintrifosfát metabolismus   MeSH
• energetický metabolismus účinky léků   MeSH
• flagella účinky léků   metabolismus   ultrastruktura   MeSH
• glykolýza účinky léků   MeSH
• kyselina pyrohroznová metabolismus   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• metabolom účinky léků   MeSH
• mikrotělíska účinky léků   metabolismus   ultrastruktura   MeSH
• mitochondrie účinky léků   metabolismus   ultrastruktura   MeSH
• molekulární modely MeSH
• prolin metabolismus   MeSH
• proteom metabolismus   MeSH
• protonové ATPasy metabolismus   MeSH
• protozoální proteiny metabolismus   MeSH
• suramin farmakologie   MeSH
• Trypanosoma brucei brucei metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfát MeSH
• kyselina pyrohroznová MeSH
• prolin MeSH
• proteom MeSH
• protonové ATPasy MeSH
• protozoální proteiny MeSH
• suramin MeSH