EVIDENCE FOR THE SHIKIMATE PATHWAY IN APICOMPLEXAN PARASITES

Parasites of the phylum Apicomplexa cause substantial morbidity, morta lity and economic losses, and new medicines to treat them are needed u rgently(1,2). The shikimate pathway is an attractive target for herbic ides and antimicrobial agents because it is essential in algae, higher plants, bacteria and fungi, but absent from mammals(3,4). Here we pre sent biochemical, genetic and chemotherapeutic evidence for the presen ce of enzymes of the shikimate pathway in apicomplexan parasites. In v itro growth of Toxoplasma gondii, Plasmodium falciparum (malaria) and Cryptosporidium parvum was inhibited by the herbicide glyphosate, a we ll-characterized inhibitor(3) of the shikimate pathway enzyme 5-enolpy ruvyl shikimate 3-phosphate synthase. This effect on T. gondii and P. falciparum was reversed by treatment with p-aminobenzoate, which sugge sts that the shikimate pathway supplies folate precursors for their gr owth. Glyphosate in combination with pyrimethamine limited T. gondii i nfection in mice. Four shikimate pathway enzymes were detected in extr acts of I: gondii and glyphosate inhibited 5-enolpyruvyl shikimate 3-p hosphate synthase activity. Genes encoding chorismate synthase, the fi nal shikimate pathway enzyme, were cloned from T. gondii and P.falcipa rum This discovery of a functional shikimate pathway in apicomplexan p arasites provides several targets for the development of new antiparas ite agents.