Published online 2 July 1998 | Nature | doi:10.1038/news980702-2

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Could malaria be killed by a garden weedkiller?

The parasites that cause malaria, toxoplasmosis and cryptosporidiosis are all members of a group of microorganisms known as the Apicomplexa. This group of parasites kills well over one million people each year, and includes some of the most common opportunistic infections of AIDS patients. New medicines to treat these infections are needed urgently.

In the 25 June 1998 issue of Nature one team of researchers describe how they are well on the way to finding such a treatment. The downfall of the Apicomplexa might turn out to be a common herbicide.

A herbicide may sound like a strange treatment for a parasitic microorganism. But plants and many microorganisms share a common biochemical pathway that other living forms - notably humans - don’t have. An agent that disables this pathway will kill plants and microorganisms, but will be completely harmless to humans.

Rima McLeod of the Michael Reese Hospital and Medical Center, Chicago, and the University of Chicago, and colleagues have now found that apicomplexans share this biochemical pathway too - known as the shikimate pathway. “This discovery of a functional shikimate pathway in apicomplexan parasites provides several targets for the development of new antiparasite agents,” say the researchers.

They first suspected that the pathway was present when they found that the apicomplexan parasites at certain stages of their life-cycle contained structures that looked just like a structure found in plants. The structure, known as a plastid, is the site for many of the important biochemical pathways, where starch, lipids, folic acid, and amino acids (the building blocks of proteins) are made.

The shikimate pathway makes the precursor for folic acid and some essential amino acids, and should, according to the researchers, be one of the pathways found inside the plastid-like structures. We humans can survive without the pathway by including the products in our diet. But this isn’t an option for plants and microorganisms. Disabling any of the seven enzyme-assisted steps along the pathway could kill the organism.

A common herbicide called glyphosate inhibits one particular enzyme in the shikimate pathway. McLeod and colleagues now show that glyphosate can slow the growth of laboratory cultures of Plasmodium falciparum (the malaria parasite), Toxoplasma gondii (which causes toxoplasmosis), and Cryptosporidium parvum (which causes cryptosporidiosis, a form of diarrhoea). Unfortunately, because gyphosate doesn’t kill the organisms outright, a drug treatment will need something more.

To find exactly which of the shikimate pathway products was most important to the survival of these microorganisms, the researchers added folic acid or the amino acid products, one by one, as they treated the parasites with glyphosate. The parasites seemed particularly sensitive to the lack of folic acid, so the researchers thought that they might improve the effectiveness of treatment by using glyphosate in conjunction with a conventional anti-folate medicine.

As suspected, when they tested this combination of treatments against Toxoplasma gondii, they found it to be more effective at stopping growth than either treatment alone.

But treating laboratory cultures of these organisms is one thing. Are these treatments effective for a real infection? The drugs haven’t yet been tested in humans, but the research team did try out the treatment on mice infected with the Toxoplasmosis parasite. Without treatment the infection is fatal, and anti-folate medicines alone are ineffective.

But the combination of glyphosate and anti-folate drugs saved the lives of more than half of the infected mice. The other encouraging result was that at the doses needed to treat the infection, glyphosate seemed to have no adverse effects on the mouse tissue.

The researchers conclude that ‘such combinations should be useful for the treatment of toxoplasmosis. Furthermore, they could also have applications against other diseases caused by apicomplexan parasites, such as malaria.”

The researchers have also found other shikimate-pathway enzymes in T. gondii and P. falciparum, each one a potential target for new drugs, and plan to try other new combinations of treatment. They have worked out the genetic sequences of a gene that produces one of these enzymes, which may turn out to be a powerful tool in the hunt for a ‘designer’ drug.

One real advantage of this approach to treatment will be for AIDS patients. Because the immune system of these patients is suppressed they often suffer from multiple opportunistic infections, including pneumonia and tuberculosis, as well as some of the apicomplexan infections. As all of these organisms also have the shikimate pathway, the researchers say “there is now the exciting possibility that compounds with broad-spectrum activity could be useful against several opportunistic pathogens.”