Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan
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Bilsland, E., van Vliet, L., Williams, K., Feltham, J., Carrasco, M., Fotoran, W., Cubillos, E., et al. (2018). Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan. Scientific Reports, 8 (1038)https://doi.org/10.1038/s41598-018-19549-x
Malaria, caused by parasites of the genus Plasmodium, leads to over half a million deaths per year, 90% of which are caused by Plasmodium falciparum. P. vivax usually causes milder forms of malaria; however, P. vivax can remain dormant in the livers of infected patients for weeks or years before re-emerging in a new bout of the disease. The only drugs available that target all stages of the parasite can lead to severe side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; hence, there is an urgent need to develop new drugs active against blood and liver stages of the parasite. Different groups have demonstrated that triclosan, a common antibacterial agent, targets the Plasmodium liver enzyme enoyl reductase. Here, we provide 4 independent lines of evidence demonstrating that triclosan specifically targets both wild-type and pyrimethamine-resistant P. falciparum and P. vivax dihydrofolate reductases, classic targets for the blood stage of the parasite. This makes triclosan an exciting candidate for further development as a dual specificity antimalarial, which could target both liver and blood stages of the parasite.
This work was supported by: the UK Biotechnology and Biological Sciences Research Council (BB/F008228/1) and a contract from the European Commission under the FP7 Collaborative Programme, UNICELLSYS, both to S.G.O. and R.D.K.; the Bill and Melinda Gates foundation (Op1087646 to EB and SGO), São Paulo Research Foundation - FAPESP (2012/23306-5 to WLF, EFGC and GW and 2015/19103-0 and 2015/03553-6 to EB), the ERC (208813 to FH).
ABERYSTWYTH UNIVERSITY (FB BBSRC) (BB/F008228/1)
EC FP7 CP (201142)
Bill & Melinda Gates Foundation (OPP1087646)
European Research Council (208813)
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External DOI: https://doi.org/10.1038/s41598-018-19549-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/270500