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Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen
Anjan Debnath1, Josefino B Tunac, Silvia Galindo-Gómez
1Sandler Center for Drug Discovery, University of California, San Francisco, California, USA.
Abstract:
Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species Naegleria gruberi. Five kinase inhibitors and an NF-kappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against Naegleria than that of amphotericin B. Transmission electron microscopy of N. fowleri trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae. In vivo efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM.
Insights
A new drug, corifungin, shows promise for treating primary amebic meningoencephalitis (PAM). It effectively kills Naegleria fowleri and offers a safer, more effective alternative to amphotericin B in preclinical studies.
Area of Science:
- Infectious Diseases
- Drug Discovery
- Microbiology
Background:
- Primary amebic meningoencephalitis (PAM) is a rare but almost invariably fatal infection caused by Naegleria fowleri.
- Current treatment with amphotericin B has significant toxicity and limited efficacy, necessitating new therapeutic options.
Purpose of the Study:
- To develop and validate a high-throughput screening method for identifying novel drugs against Naegleria species.
- To evaluate the efficacy of identified drug candidates, including corifungin, against Naegleria fowleri.
Main Methods:
- Automated, high-throughput screening of compound libraries against Naegleria gruberi.
- In vitro testing of promising compounds, including corifungin, against Naegleria fowleri trophozoites using transmission electron microscopy.
- In vivo efficacy studies in a mouse model of PAM.
Main Results:
- Corifungin demonstrated higher in vitro activity against Naegleria than amphotericin B, causing membrane disruption and amebic lysis.
- In vivo studies showed 100% survival in mice treated with corifungin, with no detectable amebae in the brain.
- Amphotericin B treatment did not reduce ameba growth and compromised mouse survival.
Conclusions:
- Corifungin is a potent and effective therapeutic agent against Naegleria fowleri, showing superior efficacy and safety compared to amphotericin B.
- Corifungin has received orphan drug status from the U.S. FDA for the treatment of PAM, indicating its potential as a life-saving medication.
