Folate Antagonists and Mechanisms of Resistance

Abstract

The antifolates were once thought to be a nearly ideal class of antimalarial agent (1). Antifolate drugs interfere differentially with folate metabolism, an essential parasite pathway that includes enzymes with no human counterparts. They are effective both as prophylactic and therapeutic agents against malaria. However, the antifolates are notoriously quick to fall prey to resistant parasites, and resistance to the commercially available antifolates is now widespread. The most popular formulation, sulfadoxine—pyrimethamine, is no longer recommended for general prophylaxis because of rare but serious cutaneous drug reactions. Are the antifolates a class of antimalarials whose time has come and gone? Most emphatically not, for the following reasons: First, sulfadoxine—pyrimethamine is currently the first-line antimalarial drug in several sub-Saharan African countries where chloroquine resistance is widespread and where other drugs remain far too expensive for general use. Second, several promising new combinations of antifolates that may be less susceptible to parasite resistance and less toxic are in development. Finally, new metabolic pathways that can be targeted with drugs that may behave synergistically with the antifolates have recently been identified in Plasmodium species (e.g., the shikimate pathway) (2), and many such discoveries can be anticipated as the malariagenome-sequencing project proceeds. The antifolate antimalarials will remain in widespread use for the foreseeable future because of a lack of affordable alternatives and will remain one of the major classes of new drugs under development because of their high therapeutic index and their synergy with each other and with other drugs.