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Sequenced malaria genome exposes novel drug targets

University of Melbourne

The genetic code of the malaria parasite has been cracked and is already revealing novel drug targets that could lead to effective treatment of the disease.

An international effort was launched in 1996 to sequence the genome of the most deadly malaria species, Plasmodium falciparum. Botanists from the University of Melbourne are now leading the charge to help find safe and effective anti-malarial drugs.

Professor Geoff McFadden and his team from the University of Melbourne recently discovered that the malaria parasite evolved from a plant-like organism that survived by photosynthesis. It is this plant-like part that, so far, appears to be a depot for anti-malarial drug targets. Consequently, existing safe herbicides are providing leads for some of these new drugs. So too are antibiotics.

"Our role in this international collaboration is to find the genes associated with the relict plant component of the parasite. This has been a key success of the study. At least 12 new drug targets have been identified so far from the plant-like genes" says McFadden.

The collaboration's research, including the complete sequence of the malaria parasite, is published in the latest edition of the prestigious journal Nature.

Human malaria is caused by infection with parasites of the Plasmodium species that are transmitted by Anopheles mosquitoes.

Plasmodium species are members of large group numbering over 5000 species that harbour a relict chloroplast, the part of a plant that carries out photosynthesis. Scientists have determined this relict, called the apicoplast, is essential for the malaria parasite's survival, but its exact role is unclear.

McFadden's team has gone someway to unraveling the apicoplast's mysteries. They have revealed that it is the apicoplast that houses the herbicide-sensitive pathways and compounds with potential for drug therapy. Stuart Ralph, a PhD student in McFadden's lab, has helped identify three metabolic pathways in the apicoplast that are distinct from metabolic pathways in humans or the mosquito.

Ralph, an author on the Nature paper, emphasises that that actual plant-killing ingredients of many herbicides are relatively low in their toxicity to humans. These same ingredients are showing promise in trials against the parasite.

"By finding the genes responsible for making the proteins involved in these and other unique apicoplast pathways, we can identify potential targets for drug therapy, says Ralph.

And the number of potential targets is large. Of the 5,000 genes sequenced in the malaria parasite, over ten percent (551) encode proteins associated with the apicoplast.

Chloroplasts themselves evolved from bacteria, opening the door to another common drug treatment, antibiotics. Doxycycline is a common and effective anti-malarial in use today and it is an antibiotic.

"People used it because it worked, but until now nobody knew how," says Ralph.

"We anticipate the same problems with resistance to herbicides and antibiotics as we face now, but we enter this armed with an extensive knowledge of how plants and bacteria develop resistance to these compounds. Forewarned is forearmed," he says.

McFadden and Ralph's work has implications for treatment of other devastating diseases that are also part of the group related to the malarial parasite. These include Toxoplasmosis, caused by the Toxoplasma parasite. Toxoplasma is an opportunistic parasite that can be fatal in people with compromised immune systems, such as those with HIV. Toxoplasma in pregnancy can also lead to foetal brain defects or miscarriage.

The genome of humans, and now the Anopheles mosquito (see Science 4 October 2002), and the deadliest species of malaria have been sequenced.

"For the first time, a wealth of information is available for all three species that comprise the life cycle of the malaria parasite. This provides us with abundant opportunities for the study of each species and their complex interactions that result in disease," says Ralph.

"This technology will also enable sampling of parasite, mosquito, and human genomes in malaria affected areas, providing information to support the development, deployment and monitoring of malaria control methods," he says.

Approximately 40% of the world's population lives in areas where malaria is transmitted. There are an estimated 300-500 million cases and at least 1 million deaths from malaria each year.

Recent studies suggest that the number of malaria cases may double in 20 years if new methods of control are not devised and implemented.

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