HMG-CoA Reductase Inhibitors as Drug Leads against <i>Naegleria fowleri</i>

Abstract

Primary amebic meningoencephalitis (PAM), caused by the free-living ameba <i>Naegleria fowleri</i>, has a fatality rate of over 97%. Treatment of PAM relies on amphotericin B in combination with other drugs, but few patients have survived with the existing drug treatment regimens. Therefore, development of effective drugs is a critical unmet need to avert deaths from PAM. Since ergosterol is one of the major sterols in the membrane of <i>N. fowleri</i>, disruption of isoprenoid and sterol biosynthesis by small-molecule inhibitors may be an effective intervention strategy against <i>N. fowleri</i>. The genome of <i>N. fowleri</i> contains a gene encoding HMG-CoA reductase (HMGR); the catalytic domains of human and <i>N. fowleri</i> HMGR share <60% sequence identity with only two amino acid substitutions in the active site of the enzyme. Considering the similarity of human and <i>N. fowleri</i> HMGR, we tested well-tolerated and widely used HMGR inhibitors, known as cholesterol-lowering statins, against <i>N. fowleri.</i> We identified blood-brain-barrier-permeable pitavastatin as a potent amebicidal agent against the U.S., Australian, and European strains of <i>N. fowleri</i>. Pitavastatin was equipotent to amphotericin B against the European strain of <i>N. fowleri</i>; it killed about 80% of trophozoites within 16 h of drug exposure. Pretreatment of trophozoites with mevalonate, the product of HMGR, rescued <i>N. fowleri</i> from inhibitory effects of statins, demonstrating that HMGR of <i>N. fowleri</i> is the target of statins. Because of the good safety profile and availability for both adult and pediatric uses, consideration should be given to repurposing the fast-acting pitavastatin for the treatment of PAM.