The plant-like shikimate pathway, which McLeod's team found in these parasites, consists of a series of seven biochemical reactions catalyzed by seven enzymes. This pathway results in the formation of chorismate, an essential building block of folate, certain amino acids, and ubiquinone, a molecule used in energy generation.
McLeod's team showed that glyphosate, by interfering with just one of those enzymes, could block the production of folate, inhibiting parasite growth and survival. Glyphosate proved effective against malaria strains that were resistant to an anti-malarial medicine, pyrimethamine, which interrupts folate processing at a different point. To confirm the finding, they demonstrated that these folate-starved parasites could be rescued, in the test tube, by giving them folate.
Using biochemical, genetic and chemotherapeutic techniques, McLeod's team demonstrated that these parasites all utilized the shikimate pathway. They isolated and sequenced the genes for one of the shikimate pathway enzymes from Toxoplasma and a malaria parasite and demonstrated the presence of four of the seven enzymes in parasites extracts.
Finally, they tested glyphosate in mice infected with lethal doses of T.
gondii. Doses of glyphosate or pyrimethamine that could not protect the mice
when used alone rescued infected mice when used in combination, even when the
mice were allowed to eat diets with folate. "Since resistance to antimicrobial
agents is a major problem in the treatment of malaria, we were pleased to find
that combining medications in a logical way, to inhibit multiple enzymes in the
pathway, enhanced their effect," said McLeod. "This emphasized the potential
value of concomitantly targeting alternative enzymes along the sam
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Contact: John Easton
jeaston@mcis.bsd.uchicago.edu
773 702 6241
University of Chicago Medical Center
25-Jun-1998