Anti-malarial mechanism unraveled

For more than 50 years antifolate drug therapy has been used successfully to treat malaria caused by Plasmodium falciparum. It had been assumed that differences between host and parasite in terms of the drug binding to dihydrofolate reductase-thymidylate synthase (DHFR-TS) were responsible for this success. But, in 19 April Science, Kai Zhang and Pradipsinh Rathod of University of Washington, Seattle, show that it may be differences in the regulation of DHFR between host and parasite that explain the efficacy of antifolate against P. falciparum (Science 2002, 296:545-547).

Zhang and Rathod examined in vitro P. falciparum systems and observed that the parasite DHFR-TS binds its cognate mRNA and inhibits its own translation. But, unlike translational regulation of DHFR-TS in humans, DHFR-TS mRNA binding was not coupled to enzyme active sites.

"Our findings point to an important paradigm for antimicrobial drug selectivity," said the authors. "Relatively nonspecific antimetabolites can selectively inhibit pathogen ...