Folate metabolism in human malaria parasites—75 years on

•Antifolates have a long history of successful application in malaria chemotherapy.•Drug resistance depends on mutations in the dhfr and dhps genes and other factors.•A number of components of folate metabolism in P. falciparum offer novel targets.•Newer approaches will include the application of ‘omics’ technologies.•Outstanding questions include the relative roles of folate biosynthesis and salvage.

Malaria still poses one of the most serious threats to human health worldwide and the prevailing lack of effective, clinically licensed, vaccines means that prophylaxis and treatment depend heavily on a small number of compounds whose efficacies are progressively compromised at varying rates by the inevitable emergence of drug-resistant parasite populations. Of these antimalarials, those inhibiting steps in folate metabolism, along with chloroquine, are the oldest synthetic compounds, with origins dating back three-quarters of a century. Despite widespread parasite resistance, the antifolates still play an important role in malaria control, and our understanding of the underlying mechanisms of folate metabolism and genesis of drug resistance has increased considerably over the last twenty years. Folate de novo synthesis in the parasite, interconversion of active folate derivatives and their utilisation as multifunctional cofactors involve numerous enzymes, although only two of these have ever served as targets of clinical antimalarial inhibitors. The current application of antifolates, resistance to this class of drugs, new insights into folate metabolism in the parasite, its potential for providing novel targets of inhibition and some of the questions that are still outstanding are reviewed here.

Graphical abstractThe current application of antifolates to malaria parasites, resistance to these drugs, new insights into folate metabolism, its potential for providing novel targets and some outstanding questions are reviewed here.Figure optionsDownload full-size imageDownload high-quality image (120 K)Download as PowerPoint slide