Trypanosomal Dihydrofolate Reductase Reveals Natural Antifolate Resistance

2011 ◽  
Vol 6 (9) ◽  
pp. 905-911 ◽  
Author(s):  
Jarunee Vanichtanankul ◽  
Supannee Taweechai ◽  
Jirundon Yuvaniyama ◽  
Tirayut Vilaivan ◽  
Penchit Chitnumsub ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Antifolate Resistance

Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors

Parasitology ◽  
2005 ◽  
Vol 130 (3) ◽  
pp. 249-259 ◽  
Author(s):  
Y. YUTHAVONG ◽  
J. YUVANIYAMA ◽  
P. CHITNUMSUB ◽  
J. VANICHTANANKUL ◽  
S. CHUSACULTANACHAI ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Thymidylate Synthase ◽  
Structural Basis ◽  
Antifolate Resistance

scholarly journals Novel Point Mutations in the Dihydrofolate Reductase Gene of Plasmodium vivax: Evidence for Sequential Selection by Drug Pressure

2003 ◽  
Vol 47 (5) ◽  
pp. 1514-1521 ◽  
Author(s):  
Mallika Imwong ◽  
Sasithon Pukrittayakamee ◽  
Laurent Rénia ◽  
Franck Letourneur ◽  
Jean-Paul Charlieu ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Sequence Data ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Drug Pressure ◽  
Sequential Selection ◽  
Pcr Product ◽  
Reductase Gene ◽  
Antifolate Resistance ◽  
Type Sequence

ABSTRACT Mutations in the dihydrofolate reductase (dhfr) genes of Plasmodium falciparum and P. vivax are associated with resistance to the antifolate antimalarial drugs. P. vivax dhfr sequences were obtained from 55 P. vivax isolates (isolates Belem and Sal 1, which are established lines originating from Latin America, and isolates from patient samples from Thailand [n = 44], India [n = 5], Iran [n = 2], and Madagascar [n = 2]) by direct sequencing of both strands of the purified PCR product and were compared to the P. vivax dhfr sequence from a P. vivax parasite isolated in Pakistan (isolate ARI/Pakistan), considered to represent the wild-type sequence. In total, 144 P. vivax dhfr mutations were found at only 12 positions, of which 4 have not been described previously. An F→L mutation at residue 57 had been observed previously, but a novel codon (TTA) resulted in a mutation in seven of the nine mutated variant sequences. A new mutation at residue 117 resulted in S→T (S→N has been described previously). These two variants are the same as those observed in the P. falciparum dhfr gene at residue 108, where they are associated with different levels of antifolate resistance. Two novel mutations, I→L at residue 13 and T→M at residue 61, appear to be unique to P. vivax. The clinical, epidemiological, and sequence data suggest a sequential pathway for the acquisition of the P. vivax dhfr mutations. Mutations at residues 117 and 58 arise first when drug pressure is applied. Highly mutated genes carry the S→T rather than the S→N mutation at residue 117. Mutations at residues 57 and 61 then occur, followed by a fifth mutation at residue 13.

Drosophila dihydrofolate reductase mutations confer antifolate resistance to mammalian cells

2006 ◽  
Vol 529 (1-3) ◽  
pp. 71-78 ◽  
Author(s):  
Joslynn G. Affleck ◽  
Khalid M. Al-Batayneh ◽  
Katerina Neumann ◽  
Susan P.C. Cole ◽  
Virginia K. Walker
Keyword(s):  
Dihydrofolate Reductase ◽  
Mammalian Cells ◽  
Antifolate Resistance

scholarly journals Defining the Role of Mutations in Plasmodium vivax Dihydrofolate Reductase-Thymidylate Synthase Gene Using an Episomal Plasmodium falciparum Transfection System

2010 ◽  
Vol 54 (9) ◽  
pp. 3927-3932 ◽  
Author(s):  
Alyson M. Auliff ◽  
John H. Adams ◽  
Michael T. O'Neil ◽  
Qin Cheng
Keyword(s):  
Plasmodium Vivax ◽  
Dihydrofolate Reductase ◽  
Thymidylate Synthase ◽  
Resistance Index ◽  
Rapid Screening ◽  
Compensatory Mutation ◽  
Wild Type ◽  
Triple Mutant ◽  
Antifolate Drugs ◽  
Antifolate Resistance

ABSTRACT Plasmodium vivax resistance to antifolates is prevalent throughout Australasia and is caused by point mutations within the parasite dihydrofolate reductase (DHFR)-thymidylate synthase. Several unique mutations have been reported in P. vivax DHFR, and their roles in resistance to classic and novel antifolates are not entirely clear due, in part, to the inability to culture P. vivax in vitro. In this study, we use a homologous system to episomally express both wild-type and various mutant P. vivax dhfr (pvdhfr) alleles in an antifolate-sensitive line of P. falciparum and to assess their influences on the susceptibility of the recipient P. falciparum line to commonly used and new antifolate drugs. Although the wild-type pvdhfr-transfected P. falciparum line was as susceptible to antifolate drugs as the P. falciparum parent line, the single (117N), double (57L/117T and 58R/117T), and quadruple (57L/58R/61M/117T) mutant pvdhfr alleles conferred a marked reduction in their susceptibilities to antifolates. The resistance index increased with the number of mutations in these alleles, indicating that these mutations contribute to antifolate resistance directly. In contrast, the triple mutant allele (58R/61M/117T) significantly reversed the resistance to all antifolates, indicating that 61M may be a compensatory mutation. These findings help elucidate the mechanism of antifolate resistance and the effect of existing mutations in the parasite population on the current and new generation of antifolate drugs. It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax.

Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: structural basis of antifolate resistance

2000 ◽  
Vol 8 (5) ◽  
pp. 1117-1128 ◽  
Author(s):  
Giulio Rastelli ◽  
Worachart Sirawaraporn ◽  
Pornthep Sompornpisut ◽  
Tirayut Vilaivan ◽  
Sumalee Kamchonwongpaisan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Structural Basis ◽  
Antifolate Resistance
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