Primary amebic meningoencephalitis, caused by brain
infection with a free-living ameba, Naegleria fowleri, leads to extensive
inflammation of the brain and death within 3-7 days after symptoms begin. Treatment of
primary amebic meningoencephalitis relies on
amphotericin B in combination with other drugs, but use of
amphotericin B is associated with severe adverse effects. Despite a fatality rate of over 97%, economic incentive to invest in development of antiamebic drugs by the pharmaceutical industry is lacking. Development of safe and rapidly acting drugs remains a critical unmet need to avert future deaths. Since FDA-approved anti-inflammatory and antiarthritic
drug auranofin is a known inhibitor of
selenoprotein synthesis and
thioredoxin reductase and the genome of N. fowleri encodes genes for both
selenocysteine biosynthesis and
thioredoxin reductases, we tested the effect of
auranofin against N. fowleri strains of different genotypes from the USA, Europe, and Australia.
Auranofin was equipotent against all tested strains with an EC50 of 1-2 μM. Our growth inhibition study at different time points demonstrated that
auranofin is fast-acting, and ∼90% growth inhibition was achieved within 16 h of
drug exposure. A short exposure of N. fowleri to
auranofin led to the accumulation of intracellular
reactive oxygen species. This is consistent with
auranofin's role in inhibiting
antioxidant pathways. Further, combination of
auranofin and
amphotericin B led to 95% of growth inhibition with 2-9-fold
dose reduction for
amphotericin B and 3-20-fold
dose reduction for
auranofin.
Auranofin has the potential to be repurposed for the treatment of
primary amebic meningoencephalitis.