The Evolving Arsenal Against Naegleria Fowleri: From Empirical Poly-Chemotherapy to Target-Driven Repurposing Pipelines

Primary Amoebic Meningoencephalitis (PAM), caused by the thermophilic free-living amoeboflagellate Naegleria fowleri, is a hyperacute, devastating central nervous system infection characterized by rapid clinical progression and a fatal outcome exceeding 95% to 97% mortality globally. Current clinical management relies heavily on empirical poly-chemotherapy centered around intravenous amphotericin B, oral miltefosine, and azithromycin; however, these regimens are severely constrained by dose-limiting nephrotoxicity and hepatotoxicity, variable blood-brain barrier penetration, and therapeutic delays. This review provides a comprehensive synthesis of emerging small-molecule discovery pipelines, novel intracellular target landscapes, and advanced non-invasive therapeutic vectors against N. fowleri. In this review, we discuss key enzymatic bottlenecks, including glucokinase, enolase, protein farnesyltransferase, and sterol 14- -demethylase ( ) and high-throughput phenotypic screening platforms that distinguish immediate-onset clearing agents (e.g., posaconazole, nitroxoline) from high-potency candidates with extended kinetic lag phases (e.g., azithromycin). We further assess potent synthetic chemicals (bis-benzimidazoles), natural product saponins, marine meroterpenoids and oxasqualenoid polyethers that exhibit stage-independent trophocidal and cysticidal clearance against N. fowleri. For the reason prevention is better than cure in many instances, we also describe rational multi-epitope mRNA vaccine designs, as well as novel transcribrial delivery systems, such as pressurized vaporized nasal inhalers and terpene-silver nanoconjugate fusions that exploit the naso-olfactory and glymphatic pathways to bypass systemic toxicity. Transitioning from historical empirical cocktails toward target-driven, rapid-acting, and locally delivered chemotypes offers a definitive paradigm shift to improve survival and clinical outcomes in PAM.