Enolase inhibitors as therapeutic leads for Naegleria fowleri infections

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Project Summary Human infection by the pathogenic free-living amoeba Naegleria fowleri causes primary amebic meningoencephalitis (PAM), which in the majority (>95%) of infections end in fatality. We have recently found that a group of phosphonate inhibitors of the glycolytic enzyme enolase (ENO) that are well-tolerated in mammals are potent anti-amebic compounds. The goal of this proposal is to test the hypothesis that the amoeba ENO (NfENO) is a promising target for therapeutic development and to optimize phosphonate inhibtors to early lead stage. As part of this, we will use a small collection of inhibitors and a series of orthologous assays to biochemically validate NfENO as target of the agents and will determine the effect of the inhibitors on amoebae infections in a rodent disease model, scoring the immune response to treatment as part of the effort.