Thiamine utilisation as an antimalarial drug target

23 July 2013

The malaria parasite’s requirement for thiamine (vitamin B1) can be targeted for the development of novel antimalarial drugs.

Scientists at the Research School of Biology, the Australian National University (ANU) and the Bernhard Nocht Institute for Tropical Medicine (BNI), Germany have discovered that the malaria parasite’s requirement for thiamine (vitamin B1) can be targeted for the development of novel antimalarials.

In the study, which was published in recent issue of Nature Communications, the scientists genetically modified malaria parasites to overexpress enzymes involved in thiamine metabolism or thiamine-cofactor utilization and showed that these parasites had altered sensitivity to the thiamine analogue oxythiamine.

“We were amazed to find that parasites overexpressing the enzyme responsible for converting thiamine into its active cofactor were more than a thousand fold more sensitive to oxythiamine” said Audrey Chan, a PhD student at the ANU and one of the two lead authors of the paper.

“This is consistent with oxythiamine being metabolised by the parasite to produce a non-functional cofactor which then goes on to inhibit thiamine-dependent enzymes” said Carsten Wrenger (BNI), the other lead author.

“Overexpressing enzymes that require the thiamine cofactor, however, renders the parasite resistant to oxythiamine, by as much as 15 fold” said Ingrid Müller (BNI), one of the study’s senior authors. “This suggested to us that the non-functional cofactor was binding to these enzymes - we were able to demonstrate this directly”.

Malaria kills almost a million people each year, most of them children under the age of five years, and the parasite has managed to develop resistance to most of the antimalarials in clinical use. “Our demonstration that a single drug targets multiple enzymes within the parasite, some of which reside in distinct organelles, is exciting because we predict that it will be harder for the parasite to develop resistance to such a drug” said Kevin Saliba (ANU), one of the senior authors of the study. “Our validation of a new antimalarial drug target is also critically important because we need to continue to develop new drugs to fight this scourge”.

The work was supported by a grant from Go8/DAAD.

Image credit: Johns Hopkins Malaria Research Institute.

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