Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen
Open Access
- 1 November 2012
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 56 (11), 5450-5457
- https://doi.org/10.1128/aac.00643-12
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.Keywords
This publication has 41 references indexed in Scilit:
- A high-throughput drug screen for Entamoeba histolytica identifies a new lead and targetNature Medicine, 2012
- Amebic meningoencephalitides and keratitis: challenges in diagnosis and treatment*Current Opinion in Infectious Diseases, 2010
- A luciferase based viability assay for ATP detection in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427Parasites & Vectors, 2009
- Effect of Therapeutic Chemical Agents In Vitro and on Experimental Meningoencephalitis Due to Naegleria fowleriAntimicrobial Agents and Chemotherapy, 2008
- Compound Cytotoxicity Profiling Using Quantitative High-Throughput ScreeningEnvironmental Health Perspectives, 2008
- Structural genomics and drug discovery: all in the familyCurrent Opinion in Chemical Biology, 2008
- Synergistic Activities of Azithromycin and Amphotericin B against Naegleria fowleri In Vitro and in a Mouse Model of Primary Amebic MeningoencephalitisAntimicrobial Agents and Chemotherapy, 2007
- NF-κB signaling blockade by Bay 11-7085 during early cardiac morphogenesis induces alterations of the outflow tract in chicken heartApoptosis, 2006
- Drug repositioning: identifying and developing new uses for existing drugsNature Reviews Drug Discovery, 2004
- Successful Treatment of Primary Amebic MeningoencephalitisNew England Journal of Medicine, 1982