title: Anti-folate combination therapies and their effect on the development of drug resistance in Plasmodium vivax.
abstract: Can we predict the rise and spread of resistance to multi-drug therapy in a more predictable manner? We raise this question after analyzing over 500 Plasmodium vivax isolates collected from different, geographically isolated regions of China for sequence variation in and around the dhfr and dhps genes. We find: that resistance lineages have arisen at least once in each region; that there appears to have been little movement of parasite populations between these areas; and that highly resistant parasites contain dhfr and dhps alleles that are in linkage disequilibrium. We show a direct relationship between this linkage disequilibrium and a parasite's fitness in the absence of drug pressure. Such fitness would increase the spread of drug resistant phenotypes and is thus a selectable trait. These conclusions raise questions about the appropriate use of some other drug combinations to prevent and treat infection.
authors.affiliation: Department of Pathogen Biology, Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Ding
authors.forename: Run
authors.initials: R
authors.lastname: Ye
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Sun
authors.forename: Hongning
authors.initials: H
authors.lastname: Zhou
authors.forename: Thomas F
authors.initials: TF
authors.lastname: McCutchan
authors.forename: Weiqing
authors.initials: W
authors.lastname: Pan
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D002681:China; D004338:Drug Combinations; D004351:Drug Resistance / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D014644:Genetic Variation; D005838:Genotype; D015810:Linkage Disequilibrium; D008715:Methionine / Q000096:biosynthesis; D018895:Microsatellite Repeats / Q000235:genetics; D010966:Plasmodium vivax / Q000187:drug effects* / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D013938:Thymidine Monophosphate / Q000096:biosynthesis
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D013938:Thymidine Monophosphate; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D008715:Methionine; D000426:Alcohol Dehydrogenase; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine