Analysis of two screens reveals a correlation between antiamoebic and anti-tubulin activities of phenothiazine and triphenylethylene derivatives.

Naegleria fowleri (N.f.), commonly referred to as the "brain-eating amoeba", is a free-living amoeboflagellate excavate capable to cause primary amoebic meningoencephalitis (PAM)-a rapidly progressing and typically fatal brain infection. Current treatment options are limited, poorly effective, and highly toxic, underscoring the urgent need for novel therapeutics. In this study, we explore the potential of repurposing FDA-approved microtubule-targeting agents (MTAs) for anti-N.f. therapy. By performing a comparative analysis of two large-scale drug screens-one assessing anti-amoebic activity and the other evaluating effects on tubulin polymerization-we identify strong correlations between microtubule disruption and amoebic growth inhibition. Notably, we highlight three major drug families (triphenylethylene, phenothiazine, and miconazole derivatives) and describe how their anti-amoebic effects relate to their MTA activity. In particular, triphenylethylene and phenothiazine compounds demonstrate a high positive correlation between tubulin polymerization inhibition and N.f. suppression, suggesting a shared molecular mechanism. Furthermore, we identify potent MTAs such as ebselen and auranofin-both capable of crossing the blood-brain barrier-as promising candidates for repurposing. These findings demonstrate the value of MTA-based screening in anti-amoebic drug discovery and point toward new therapeutic avenues for treating this devastating disease.