The Activity of FDA-Approved Prodrug Isavuconazonium Sulfate and Its Major Metabolite Isavuconazole Against Naegleria fowleri

TL;DR

This study explores the effectiveness of isavuconazonium and its metabolite isavuconazole against the deadly amoeba Naegleria fowleri, suggesting they could be promising treatments for a rare but fatal brain infection.

Contribution

The study evaluates the antiamoebic activity of an FDA-approved antifungal prodrug and its metabolite against Naegleria fowleri for potential repurposing in treating PAM.

Findings

Isavuconazole showed potent activity against N. fowleri with minimal toxicity to mammalian cells.

Combining isavuconazole or isavuconazonium with amphotericin B was synergistic and non-toxic to mammalian cells.

Both compounds achieved nanomolar potency after 24 hours of exposure.

Abstract

Objectives: Free-living amoeba Naegleria fowleri causes primary amoebic meningoencephalitis (PAM). While infection is rare, PAM’s fatality rate exceeds 97%. The recommended treatment includes combination therapy, which does not result in uniform survival. Thus, there is a critical unmet need for finding better therapy for PAM. Drug repurposing can expedite the discovery of effective treatment for PAM. Isavuconazonium is approved for the treatment of fungal infections. Given that isavuconazole is the major metabolite of isavuconazonium and isavuconazole penetrates into the brain with high efficiency, our objective was to determine the activity of both isavuconazonium and isavuconazole on N. fowleri trophozoites. Methods: To test the effect of both compounds, we determined their dose–responses against N. fowleri and two mammalian cells. To establish how fast the prodrug and the metabolite kill the trophozoites, we measured potency at different time points. Finally, we investigated the effect of combining isavuconazonium or isavuconazole with amphotericin B on both N. fowleri and mammalian cells. Results: Both isavuconazonium and the metabolite isavuconazole were active against multiple strains, with clinically relevant isavuconazole exhibiting potency ranging between 0.1 and 0.6 µM. They were less toxic on mammalian cells. Isavuconazonium and isavuconazole required 24 h to achieve nanomolar potency. Combination with amphotericin B was synergistic without eliciting toxicity on mammalian cells. Conclusions: Our findings, together with the use of intravenous and oral formulations of isavuconazonium to treat pediatric and adult patients, support further in vivo efficacy study of isavuconazonium for its potential use for the treatment of PAM.

Figures