Journal
PATHOGENS
Volume 9, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/pathogens9090689
Keywords
Naegleria fowleri; free-living amoeba; primary amoebic meningoencephalitis; lonafarnib; pitavastatin; farnesyltransferase; 3-hydroxy-3-methyl-glutaryl-CoA reductase
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Funding
- UC San Diego Frontiers of Innovation Scholars Program [1KL2TR001444, 1R21AI146460]
- NIH
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Free-living amoebaNaegleria fowlericauses a rapidly fatal infection primary amebic meningoencephalitis (PAM) in children. The drug of choice in treating PAM is amphotericin B, but very few patients treated with amphotericin B have survived PAM. Therefore, development of efficient drugs is a critical unmet need. We identified that the FDA-approved pitavastatin, an inhibitor of HMG Co-A reductase involved in the mevalonate pathway, was equipotent to amphotericin B againstN. fowleritrophozoites. The genome ofN. fowlericontains a gene encoding protein farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway. Here, we show that a clinically advanced FT inhibitor lonafarnib is active against different strains ofN. fowleriwith EC(50)ranging from 1.5 to 9.2 mu M. A combination of lonafarnib and pitavastatin at different ratios led to 95% growth inhibition of trophozoites and the combination achieved a dose reduction of about 2- to 28-fold for lonafarnib and 5- to 30-fold for pitavastatin. No trophozoite with normal morphology was found when trophozoites were treated for 48 h with a combination of 1.7 mu M each of lonafarnib and pitavastatin. Combination of lonafarnib and pitavastatin may contribute to the development of a new drug regimen for the treatment of PAM.
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