Formiat-Nitrit-Transporter von Naegleria fowleri als Wirkstoffziel

Naegleria fowleri, a globally distributed rhizopod of the Vahlkampfiidae family, is the causative agent of primary amoebic meningoencephalitis. 97 % of the known cases are fatal due to the lack of suitable treatment. N. fowleri is mainly found in the tropics and subtropics. Infection occurs by the trophozoite form through the nasal mucosa. The parasite then travels along the olfactory nerve through the cribriform plate into the brain and causes severe tissue damage and necrosis. Here, the identification of three N. fowleri genes encoding formate-nitrite transporters, FNT1-3, is described. Recently, the group discovered the vital lactate-releasing FNT in the malaria parasite, and a novel class of small, drug-like FNT inhibitors with nanomolar antimalarial efficiency. Using selected inhibitors of the eukaryotic FNT for treatment of N. fowleri trophozoites in culture, the parasites were killed at single-digit micromolar concentrations. NfFNT1-3 share high sequence similarity with the FNT from malaria parasites, Toxoplasma gondii and other known FNT like the prokaryotic EcFocA. To test whether the compounds target the N. fowleri FNT1-3, codon-optimized open reading frames were expressed NfFNT1-3 in Saccharomyces cerevisiae yeast and Dictyostelium discoideum. However, all NfFNT1-3 proteins failed to transport the 14C-labeled monocarboxylates formate, acetate, and lactate. Nevertheless, different truncated variants of NfFNT1-3 showed improved protein production in yeast, D. discoideum and human embryonic kidney cells. The identification of FNT in N. fowleri is the basis for target-based drug development for the treatment of primary amoebic encephalitis.

Rights

Use and reproduction:

No license. The provisions of the German Copyright Act (UrhG) apply.

Please note that individual components of the publication may be subject to other licensing or copyright conditions.

Cite

Citation style:
Could not load citation form.