Evaluation of the Trithiolato-Bridged Arene Ruthenium Complex Conjugated to 9-(2-hydroxyethyl)-Adenine (OD62-18) as a Potential Treatment for Toxoplasma gondii Infection.

The apicomplexan parasite Toxoplasma gondii is a major food-borne pathogen, causing toxoplasmosis. Current treatment options are limited due to suboptimal efficacy and adverse side effects. From a library of > 300 organometallic drugs we explored the therapeutic potential of a trithiolato-bridged arene ruthenium complex conjugated to 9-(2-hydroxyethyl)-adenine (OD62-18).

OD62-18 inhibited parasite proliferation in vitro with an IC50 < 60nM, induced significant alterations in the mitochondrial matrix and the disappearance of cristae, and had a negative impact on the mitochondrial membrane potential, while the overall morphology and secretory organelles were not notably affected. Differential affinity chromatography and mass spectrometry identified the YOU2 family C2C2 zinc finger protein, a Tim10 homologue, as the primary OD62-18 binding protein. However, knockout parasites lacking TgTim10 displayed no discernible differences in growth, proliferation, or plaque formation, and maintained a similar IC50 under OD62-18 treatment. OD62-18 treatment of T. gondii oocyst infected mice resulted in only negligible effects on parasite load in various tissues, and inductively coupled plasma mass spectrometry (ICP-MS) analysis revealed predominant drug excretion after 24 hours, with no penetration into the brain.

While OD62-18 demonstrates notable in vitro efficacy against T. gondii, further investigations are necessary to address the observed in vivo limitations and optimize its therapeutic potential.