Drug resistance in malaria is thus a zealously investigated topic, covering everything from developing methods to detect emerging drug resistance to designing drugs that may prolong usefulness in the face of rapidly evolving resistance. Discovering the adaptive landscape of drug resistance provides another way to gain an understanding of how antimalarial drug resistance evolves and how the course of evolution is shaped by molecular forces. One class of antimalarials,MG132 the antifolates, works by competitively inhibiting enzymatic action in the folate pathway. Within the folate pathway the enzymes dihydrofolate reductase and dihydropteroate synthase are most often targeted for inhibition. DHFR performs the essential task of reducing dihydrofolate to tetrahydrofolate, which is a cofactor in the synthesis of purines, pyrimidines, and amino acids. DHPS is also a key component in the biosynthesis of folate, producing the product 7,8-dihydropteroate which immediately preceeds folate in the pathway. Antifolates targeting DHFR are often combined with MK-1775 sulfa-drugs aimed at DHPS and are used in combination therapies such as sulfadoxine-pyrimethamine and trimethoprim-sulfamethoxazole due to the synergistic properties of such combinations. The folate pathway is an excellent drug target due to the indispensable nature of the products of the pathway and due to the presence of fixed differences in the amino acid sequence between parasite and host that allow targeted inhibition of species-specific variants of DHFR. In the case of malaria, the species-specific differences mean that administering an antifolate drug can kill the parasite without excessive harmful side-effects to the human host. For decades the great efficacy, stability, and cost-effectiveness of the antifolate pyrimethamine had made it the first-line of defense in many developing countries plagued by malaria. Regrettably, resistance to pyrimethamine and other antifolates such as proguanil and chlorproguanil has become widespread. While sulfadoxine-pyrimethamine is still being used as Intermittent Preventative Treatment in pregnant women, although even in IPT resistance to sulfadoxine pyrimethamine has become a concern. SP has thus been largely been replaced by artemisinin combination therapies in clinical settings.