title: The evolutionary landscape of antifolate resistance in Plasmodium falciparum.
abstract: Resistance to antifolates in Plasmodium falciparum is well described and has been observed in clinical settings for decades. At the molecular level, point mutations in the dhfr gene that lead to resistance have been identified, and the crystal structure of the wildtype and mutant dihydrofolate reductase enzymes have been solved in complex with native substrate and drugs. However, we are only beginning to understand the complexities of the evolutionary pressures that lead to the evolution of drug resistance in this system. Microbial systems that allow heterologous expression of malarial proteins provide a tractable way to investigate patterns of evolution that can inform our eventual understanding of the more complex factors that influence the evolution of drug resistance in clinical settings. In this paper we will review work in Escherichia coli and Saccharomyces cerevisiae expression systems that explore the fitness landscape of mutations implicated in drug resistance and show that (i) a limited number of evolutionary pathways to resistance are followed with high probability; (ii) fitness costs associated with the maintenance of high levels of resistance are modest; and (iii) different antifolates may exert opposing selective forces.
authors.affiliation: Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Marna S
authors.initials: MS
authors.lastname: Costanzo
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hartl
mesh_terms: D000220:Adaptation, Biological; D000818:Animals; D004351:Drug Resistance / Q000235:genetics*; D019143:Evolution, Molecular; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
chemical_list: D005493:Folic Acid Antagonists; D015800:Protozoan Proteins; D013762:Tetrahydrofolate Dehydrogenase