title: Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.
abstract: BACKGROUND
  Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.
  
  
  RESULTS
  We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.
  
  
  CONCLUSIONS
  Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.
authors.affiliation: Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America. marna.costanzo@gmail.com
authors.forename: Marna S
authors.initials: MS
authors.lastname: Costanzo
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Brown
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hartl
mesh_terms: D004351:Drug Resistance; D019143:Evolution, Molecular; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000201:enzymology / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D002727:Proguanil / Q000494:pharmacology; D011739:Pyrimethamine / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology
chemical_list: D005493:Folic Acid Antagonists; D014227:Triazines; C026009:cycloguanil; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D011739:Pyrimethamine