Babesia duncani (ACE Inhibitor Fosinopril study)
Effective and safe antiparasitic drugs are urgently needed to combat the rapid emergence of drug-resistant pathogens such as Babesia parasites, the causative agents of human babesiosis. By screening a library of FDA-approved drugs against the human pathogen Babesia duncani, we identified the Angiotensin Converting Enzyme (ACE) inhibitor fosinopril, a commonly used prodrug for the treatment of hypertension and heart failure, as a potent inhibitor of parasite development within human erythrocytes. Cell biological and mass spectrometry analyses demonstrated that fosinopril transported into the parasite is converted into its diacid active molecule fosinoprilat by a parasite-encoded esterase, BdFE1. Accordingly, parasite mutants carrying a mutation L238H in the BdFE1 gene displayed reduced susceptibility to the drug. These studies highlight the potential for drug repurposing and further optimization of the class of phosphonate-containing inhibitors, as a strategy for treatment of parasitic infections.