Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen

Antimicrob Agents Chemother. 2012 Nov;56(11):5450-7. doi: 10.1128/AAC.00643-12. Epub 2012 Aug 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amebiasis / drug therapy*
  • Amebiasis / mortality
  • Amebiasis / parasitology
  • Aminoglycosides / chemistry
  • Aminoglycosides / pharmacology*
  • Amphotericin B / chemistry
  • Amphotericin B / pharmacology
  • Animals
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology*
  • Brain / drug effects
  • Brain / parasitology
  • Cell Membrane / drug effects
  • Cell Membrane / ultrastructure
  • Central Nervous System Protozoal Infections / drug therapy*
  • Central Nervous System Protozoal Infections / mortality
  • Central Nervous System Protozoal Infections / parasitology
  • Drug Administration Schedule
  • High-Throughput Screening Assays
  • Humans
  • Injections, Intraperitoneal
  • Macrolides / chemistry
  • Macrolides / pharmacology*
  • Mice
  • Microscopy, Electron, Transmission
  • Mitochondria / drug effects
  • Mitochondria / ultrastructure
  • NF-kappa B / antagonists & inhibitors
  • Naegleria / drug effects*
  • Naegleria / growth & development
  • Naegleria / ultrastructure
  • Naegleria fowleri / drug effects*
  • Naegleria fowleri / growth & development
  • Naegleria fowleri / ultrastructure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Survival Rate
  • Trophozoites / drug effects*
  • Trophozoites / growth & development
  • Trophozoites / ultrastructure


  • Aminoglycosides
  • Antiprotozoal Agents
  • Macrolides
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Amphotericin B
  • Protein Kinases
  • corifungin