In vivo experiments demonstrate the potent antileishmanial efficacy of repurposed suramin in visceral leishmaniasis

Author summary Visceral Leishmaniasis (VL) or Kala-azar, classed as a neglected tropical disease, is still a major problem worldwide, aggravated byincreasing parasitic resistance against thedrugs commonly used for its treatment. Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitroand in animal model experiments. Our study showed thatsuramin is effective againstL.donovaniand significantly reduced the (splenic/hepatic) parasitic burden inL.donovaniinfected BALB/c mice, switchingthe immune response in the infected BALB/c mice from T(H)2 to aT(H)1 type. TheITC data confirmed that suramin does indeed interact with parasitic phosphoglycerate kinase (LmPGK) and enzyme assays demonstrated the inhibition ofLmPGK due to the drug. Therefore, our investigation raises the possibility of suramin being included in the repertoire of drugs used to treat VL. Background Treatment failure and resistance to the commonly used drugsremains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitroand in animal model experiments. Methodology/Principal Leishmaniadonovanipromastigotes were treated with suramin and studieswere performed to determine the extent and mode of cell mortality, cell cycle arrest and otherinvitroparameters. In addition,L.donovaniinfected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC)and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). Findings Thein vitrostudiesrevealed the potential efficacy of suramin against theLeishmaniaparasite. This observation was further substantiated in thein vivomurine model, which demonstrated thatupon suramin administration, theLeishmaniainfected BALB/c mice were able to reduce the parasitic burden and alsogenerate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. Conclusions/Significance Allexperiments affirmed the efficacy ofsuramin againstL.donovaniinfection, which could possibly lead to its inclusion in the repertoire of drugs against VL.