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Vitamin B1 pathway could hold malaria clue

Anti-malarial clue A new anti-malarial drug that stops the malaria parasite from using vitamin B1 is now plausible, say researchers.

Pharmacologist, Dr Kevin Saliba, from the Australian National University, and colleagues, report their findings in recent issue of Nature Communications.

"We can target the pathways by which the parasite takes up the vitamin and metabolises it," says Saliba. "These pathways can serve as drug targets."

Just like humans, malaria parasites need vitamins to grow and multiply.

Thiamine (vitamin B1) is converted in cells to a cofactor, which then binds a number of enzymes involved in energy production.

Saliba and colleagues wondered whether it might be possible to inhibit this thiamine metabolism pathway.

As a 'probe drug', they used an analogue of thiamine, which looks similar to the vitamin but cannot actually be used in energy production.

To provide proof of principle they looked at what happens to the pathway involving two enzymes - oxoglutarate dehydrogenase and pyruvate dehydrogenase.

In an invitro experiment, the researchers found that the parasite metabolised the analogue into a cofactor which binds to the enzymes, but they found evidence that the analogue was inhibiting one of the enzymes.

Saliba and colleagues also gave the thiamine analogue to mice infected with malaria and found they lost weight.

"That's consistent with the drug having some toxicity," says Saliba.

He says the thiamine analogue used here would interfere with energy metabolism in humans so any anti-malarial drug based on these findings would have to be designed very carefully.

"The idea is that you come up with a drug that would selectively target the parasite pathway," says Saliba. "We would have to rely on slight differences between the human and parasite thiamine metabolism pathways."

There are currently anti-malarial drugs that target folate metabolism, says Saliba, which means there is a precedent for having a drug that targets a metabolic pathway in a pathogen that also exists in humans.

Resistance

A major problem with anti-malarials is the development of resistance.

"The malaria parasite has become resistant to just about all the drugs we've used against it," says Saliba.

He says it is exciting to have one drug that is metabolised in the parasite that targets multiple enzymes in energy metabolism.

"It will be more difficult for the parasites to become resistant to a drug that's binding to several enzymes," says Saliba.

About 3.3 billion people - almost half of the world's population - are at risk of malaria, according to the World Health Organization.