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Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan

Accepted version
Peer-reviewed

Change log

Authors

Bilsland, Elizabeth 
Van Vliet, Liisa 
Williams, Kevin 
Feltham, Jack 
Carrasco, Marta 

Abstract

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.

Description

Keywords

Antimalarials, Binding Sites, Enzyme Activation, Folic Acid Antagonists, Models, Molecular, Molecular Conformation, Plasmodium, Protein Binding, Structure-Activity Relationship, Tetrahydrofolate Dehydrogenase, Triclosan

Journal Title

Scientific Reports

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

8

Publisher

Nature Publishing Group
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/F008228/1)
European Commission (201142)
Bill & Melinda Gates Foundation (OPP1087646)
European Research Council (208813)
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).