Corifungin : a new drug lead for Naegleria, identified from a high throughput screen.

Publication Type:

Journal Article

Source:

Antimicrobial agents and chemotherapy (2012)

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 a 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 pre-clinical drug discovery pipeline, we identified Corifungin, a water-soluble polyene macrolide, with better activity against Naegleria than 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 absence of detectable ameba in brain and 100% survival of mice for 17 days post-infection at a single intraperitoneal dose of 9 mg/kg/day for 10 days. The same dose of amphotericin B did not reduce ameba growth and mouse survival was compromised. Based on these results, the USFDA has approved orphan-drug status for Corifungin in treatment of PAM.