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

Author(s):Show less -

Bilsland, Elizabeth ^{[1, 2, 3]} ; van Vliet, Liisa ^{[2, 3]} ; Williams, Kevin ^[4] ; Feltham, Jack ^{[2, 3]} ; Carrasco, Marta P. ^[5] ; Fotoran, Wesley L. ^[6] ; Cubillos, Eliana F. G. ^[6] ; Wunderlich, Gerhard ^[6] ; Grotli, Morten ^[5] ; Hollfelder, Florian ^{[7, 2, 3]} ; Jackson, Victoria ^[7] ; King, Ross D. ; Oliver, Stephen G. ^{[2, 3]}

Affiliation

^[1] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, Campinas, SP - Brazil

^[2] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge - England

^[3] Univ Cambridge, Dept Biochem, Cambridge - England

^[4] Aberystwyth Univ, Dept Comp Sci, Aberystwyth, Dyfed - Wales

^[5] Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg - Sweden

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo, SP - Brazil

^[7] Univ Manchester, Manchester Inst Biotechnol, Manchester, Lancs - England

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 8, JAN 18 2018.
• Web of Science Citations: 6

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. (AU)

• FAPESP's process: 15/03553-6 - Engineering yeast cells for drug discovery
• Grantee: Elizabeth Bilsland
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 15/19103-0 - ENGINEERING YEAST CELLS FOR DRUG DISCOVERY
• Grantee: Elizabeth Bilsland
• Support Opportunities: Scholarships in Brazil - Young Researchers
• FAPESP's process: 12/23306-5 - Studies on the mechanism of transcriptional control and switching of virulence-associated genes in Plasmodium falciparum
• Grantee: Gerhard Wunderlich
• Support Opportunities: Regular Research Grants