Inhibition of fatty acid oxidation as a new target to treat Primary Amoebic Meningoencephalitis by repurposing two well-known drugs

Abstract

Primary Amoebic Meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living amoeba Naegleria fowleri. The disease mostly affects healthy children and young adults after contaminated water enters the nose, generally during recreational water activities. The amoeba migrate along the olfactory nerve to the brain, resulting in seizures, coma and eventually death. Previous research has shown that Naegleria gruberi, a close relative of N. fowleri, prefers lipids over glucose as an energy source. Therefore, we tested several inhibitors of fatty acid oxidation alongside the currently used drugs amphotericin B and miltefosine. Our data demonstrate that etomoxir, orlistat, perhexiline, thioridazine and valproic acid inhibited growth of N. gruberi. Furthermore, additive effects were seen when drugs were combined. Both thioridazine and valproic acid inhibit in vitro growth of N. gruberi in concentrations that can be obtained at the site of infection, which is doubtful with the currently used drugs amphotericin B and miltefosine. Both thioridazine and valproic acid have already been used for other diseases. As the development of new drugs and randomized controlled trials for this rare disease is nearly impossible, repurposing drugs is the most promising way to obtain additional drugs to combat PAM. Thioridazine and valproic acid are available drugs without major side-effects and can, therefore, be used as new complementary options in PAM therapy.