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

Antimicrobial Agents and Chemotherapy
Maarten J. SarinkJaap J. van Hellemond

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, not only are lipids the preferred food source for N. gruberi, but also oxidation of fatty acids 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 ...Continue Reading

References

Aug 5, 1985·FEBS Letters·C Van den Branden, F Roels
Jun 3, 2004·Nature Reviews. Drug Discovery·David A FidockSolomon Nwaka
Apr 9, 2008·Journal of Inherited Metabolic Disease·M F B SilvaI Tavares de Almeida
Sep 4, 2008·Antimicrobial Agents and Chemotherapy·Jong-Hyun KimHo-Joon Shin
Mar 10, 2010·Cell·Lillian K Fritz-LaylinScott C Dawson
Feb 5, 2011·Emerging Infectious Diseases·Sadia ShakoorAfia Zafar
Aug 17, 2011·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·Johan F De Jonckheere
Jan 13, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Sarah K KembleRichard Danila
Jul 27, 2012·The Journal of Antimicrobial Chemotherapy·Thomas P C DorloPeter J de Vries
Aug 8, 2012·Antimicrobial Agents and Chemotherapy·Anjan DebnathJames H McKerrow
Sep 21, 2013·Annual Review of Pharmacology and Toxicology·David Horn, Manoj T Duraisingh
Jun 22, 2014·BMC Genomics·Denise C Zysset-BurriMatthias Wittwer
Aug 12, 2015·Antimicrobial Agents and Chemotherapy·Eddie GraceKris Virga
May 7, 2016·Bioinformatics·Giovanni Y Di VeroliDuncan I Jodrell
Jul 7, 2016·Journal of Medical Microbiology·Moisés Martínez-CastilloMineko Shibayama
Sep 12, 2016·Current Infectious Disease Reports·Jennifer R Cope, Ibne K Ali
Oct 30, 2016·Acta Tropica·Ruqaiyyah SiddiquiNaveed Ahmed Khan
Jul 28, 2017·Current Drug Discovery Technologies·Anshul ShakyaSurajit Kumar Ghosh
Oct 25, 2017·Anticancer Research·Borisz VargaGabriella Spengler
Feb 6, 2018·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jennifer R CopeVincent R Hill
Aug 9, 2018·PloS One·Claes Søndergaard WassmannJanne Kudsk Klitgaard
Aug 22, 2018·Scientific Reports·Mirza S BaigRajkumar Savai
Oct 13, 2018·Nature Reviews. Drug Discovery·Sudeep PushpakomMunir Pirmohamed
Nov 21, 2019·Trends in Parasitology·Sutherland K MaciverJacob Lorenzo-Morales

❮ Previous
Next ❯

Citations

Jan 27, 2021·Expert Review of Anti-infective Therapy·Anjan Debnath

❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry

Software Mentioned

GraphPad Prism
combenefit

Related Concepts

Related Feeds

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.