Inhibition of Fatty Acid Oxidation as a New Target to Treat Primary Amoebic Meningoencephalitis

Antimicrob Agents Chemother. 2020 Jun 8;AAC.00344-20. doi: 10.1128/AAC.00344-20. Online ahead of print.

Abstract

Primary Amoebic Meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living amoeba Naegleria fowleri The amoeba migrates 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 already approved 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 We then tested these compounds on N. fowleri and found etomoxir, perhexiline and thioridazine to be effective growth inhibitors. Hence, lipids are not only the preferred food source for N. gruberi, but oxidation of fatty acids also seems to be essential for growth of N. fowleri Inhibition of fatty acid oxidation could result in new treatment options, as thioridazine inhibits N. fowleri growth in concentrations that can be reached at the site of infection. It could also potentiate currently used therapy, as checkerboard assays revealed synergy between miltefosine and etomoxir. Animal testing should be performed to confirm the added value of these inhibitors. Although the development of new drugs and randomized controlled trials for this rare disease are nearly impossible, inhibition of fatty acid oxidation seems a promising strategy as we showed effectivity of several drugs that are or have been in use and thus could be repurposed to treat PAM in the future.