Optimization of delivery of HEX for treatment of primary amebic encephalitis

Project Summary Brain infections by the pathogenic free-living amoeba Naegleria fowleri are life-threatening and typically (>95% of the time) result in patient fatality. We have identified a potent inhibitor, HEX, of the amoeba enzyme enolase (NfENO), that is well-tolerated in mammals and can extend life of infected rodents. The goal of this proposal is to optimize delivery of HEX to achieve curative concentrations in the brain. To date, resolution of brain distribution has been challenging due to the small size and charged nature of HEX. Here, we will develop mass spectrometry methods required to assess brain distribution of the inhibitor which will enable optimization of delivery approaches and schedules. Additionally, we will score the value of partner drugs in the treatment of disease in a rodent model. Together, these experiments will serve as a key step in progressing HEX toward investigational new drug status for N. fowleri infections.