Treatment promises to kill malaria

November 4, 1994

Malaria kills up to five million people around the world every year. Now teams of researchers in Australia are developing new cures for an age-old menace.

The World Health Organisation's optimistic forecast of virtual global eradication of malaria by 1980, made in 1955, was prompted by the advent of new quinine-based drugs, coupled with large-scale sprayings with DDT to kill the mosquito larvae.

The disease is at its worst in history and the parasite carried by mosquitos continues to invade regions. Migrant labourers, refugees and increasing tourism are helping its spread. By 2010, the WHO estimates, the number of people suffering from malaria will have doubled.

Australian researchers in Sydney, Melbourne and Perth, working with different substances, are hopeful that the spread and the suffering might be eased. Investigators at Murdoch University and the University of Western Australia in Perth have discovered that a chemical compound devised to rid animals of intestinal worms also kills cultures of the parasite Plasmodium falciparum.

The drug, albendazole, is also effective in treating people with worms as well as those suffering from giardia, the world's most common intestinal pathogen. About one in ten city-based Australians suffer from giardia. But it is far more common in Aboriginal communities in the north where iIt is the main reason why babies and infants fail to thrive. In trials there, Murdoch University researchers found that albendazole works with few if any side effects.

The drug appears to act against a protein in giardia called tubulin that makes up the parasite's cellular skeleton or cytoskeleton. Tubulin is not only present in giardia and intestinal worms, but also in the malaria parasite. When the UWA researchers decided to test albendazole on laboratory cultures of falciparum, they found that the protozoan was destroyed.

The team includes scientists from Murdoch University's institute for molecular genetics, headed by Andrew Thompson.

"Our ability to protect people and to treat people with malaria is becoming more and more difficult. The range of drugs available is limited and resistance is developing rapidly, so we need drugs with different modes of action. It seems albendazole could fit the bill," Dr Thompson says.

Meanwhile, researchers at the University of Sydney have isolated far greater quantities than was previously thought possible of the potent anti-malarial compound qinghao, derived from a fern-like annual shrub and first described by the Chinese 2000 years ago.

Although qinghao is cultivated extensively in China, there was no way production of the plant could meet increasing global demand. About 40 tonnes a year of the quinghao derivative, qinghaosu, would be required to treat the millions of people infected.

This in turn would have needed a vast amount of plant material since a kilogram of leaves from qinghao produces only a gram of qinghaosu. And it was estimated that only 15 tonnes a year were available anyway.

At Sydney University, organic chemists Richard Haynes and Simone Vonwiller looked for new ways of obtaining the active ingredient. They found the answer in qinghao acid, one of a large number of substances in qinghao. It was ten times more abundant than qinghaosu and its concentration in dried leaves of the plant was about one per cent by weight.

The chemists eventually de-vised a laboratory method for converting the qinghao acid into qinghaosu. Dr Vonwiller says this meant the shortfall in the world's supply could be overcome. From the acid, highly-active compounds called artemether and attesunate could then be prepared. Trials have since proved how effective these two compounds are and they have now been selected by the WHO as the next generation of anti-malarial drugs.

At La Trobe University in Melbourne, a group of biochemists is collaborating with researchers at the Walter and Eliza Hall Institute in investigating how conventional quinine-type drugs actually destroy the malaria parasite. A member of the La Trobe team, Leann Tilley says that despite 40 years of chloroquin use, scientists still do not understand how it works or how the parasite developed resistance to the drug.

Although this is pure research, Dr Tilley hopes that by uncovering the way chloroquin operates at the molecular level, it will lead to the development of new anti-malarial compounds. There is also the prospect of finding a means to combat drug resistance.

For four years, the La Trobe team has been carrying out the investigation. With colleagues at the Walter and Eliza Hall Institute, the researchers have designed and synthesised a compound that mimics the action of chloroquin. The chemical has a molecule attached that can be activated by light. This is tagged with a radioactive label and added to cultures of the malaria parasite.

"Once the chemicals have been taken up by the parasite, they are photoactivated by intense ultra-violet light," Dr Tilley explains. "The photoactivated chemicals attach to the parasite proteins to which they are bound and this enables us to identify the 'targets' for a particular drug from among the thousands of other proteins."

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