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Primary Amoebic Meningoencephalitis (PAM) is caused by  Naegleria fowleri , a free-living amoeba that occasionally infects humans. While considered “rare” (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug ‘repurposing’—a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi,  N .  fowleri  has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The  N .  fowleri  genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we ( i ) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured  N .  fowleri  trophozotes, ( ii ) identified the endogenous CYP51 substrate by mass spectrometry analysis of  N .  fowleri  lipids, and ( iii ) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially ‘druggable’ target in  N .  fowleri , and conazole drugs as the candidates for assessment in the animal model of PAM.

CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)