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Plasmodium vivax malaria is less well reported and studied than the more virulent Plasmodium falciparum malaria, but it remains a cause of tremendous morbidity (1). Until recently, it was widely believed that this species was not susceptible to the dihydrofolate reductase (DHFR) inhibitors successfully utilized against P. falciparum such as pyrimethamine. However, several recent articles have challenged this concept (2–6). An article by Hastings and Sibley (7) in a recent issue of PNAS adds to this work and brings additional perspectives on the future potential role of antifolates for P. vivax. Hastings and Sibley propose that pyrimethamine and WR99210 exert opposing selection pressures on P. vivax parasites. They use an innovative approach involving the complementation of Saccharomyces cerevisiae strains that lack endogenous DHFR. Using this approach they confirm other data (4) that a class of triazine DHFR inhibitors, based on WR99210, a metabolite of a potential biguanide prodrug, designed to be active against pyrimethamine-resistant mutants of P. falciparum, is also active against P. vivax. They go on to propose that pyrimethamine and WR99210 exert opposing selection pressures on P. vivax parasites and that they therefore might form a basis for the clinical use of two DHFR inhibitors in combination to reduce the selection of resistance to both compounds. This commentary covers four main elements: (i) a background to P. vivax malaria; (ii) P. vivax resistance to existing DHFR inhibitors; (iii) a comparison of Hopkins and Sibley's work with other recent studies; and (iv) some future perspectives including an assessment of whether multiple DHFR inhibitors might find clinical use in combination. Of the four species of malaria that can infect humans, most experimental attention is directed toward P. falciparum (8, 9). It is the most abundant species and causes most of the morbidity associated …

Chemotherapeutic hope on the horizon for Plasmodium vivax malaria?