Linked Life Data

11551635

Source:http://linkedlifedata.com/resource/pubmed/id/11551635

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2001-9-11
pubmed:abstractText
We have expressed dhfr alleles of Plasmodium falciparum in the budding yeast, Saccharomyces cerevisiae, and used this yeast model to identify single amino acid substitutions that confer high level pyrimethamine resistance on the background of the triple mutant dhfr (I51+R59+N108). Mutations in three clusters were identified: codons 50-57, 187-193, and 213-214. Several mutations previously identified in field samples were also isolated, including codons 50 and 164. The I164L mutation is of particular interest, because the quadruple mutant genotype (N51I+C59R+S108N+I164L) encodes an enzyme that is no longer inhibited by pyrimethamine, rendering sulfadoxine/pyrimethamine (SP; Fansidar) clinically ineffective. Thirty-six novel alleles were tested to determine their sensitivity to chlorcycloguanil and WR99210, two DHFR inhibitors that are in clinical and pre-clinical development, respectively. Chlorcycloguanil is effective against parasites that carry the triple mutant allele, but in vitro analysis has suggested that chlorcycloguanil will be clinically ineffective against parasites that carry the quadruple mutant allele of dhfr. In our screen, 23 of 36 novel strains were as resistant to chlorcycloguanil as the quadruple mutant, and one strain was 10-fold more resistant. WR99210 is still effective in the nM range against parasites that carry the quadruple mutant allele. In the preliminary screen, 31 of 36 novel alleles were as sensitive to WR99210 as the quadruple mutant. Detailed analysis of the remaining five showed that four of the five had IC(50) values in the same range as the quadruple mutant, and one, N51I+C59R+S108N+E192G, had an IC(50) value about fivefold higher. This result suggests that WR99210 and related compounds will be clinically effective against quadruple mutants currently found in Southeast Asia and South America and against most novel alleles that could be selected on the background of the triple mutant genotype now prevalent in East Africa.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0166-6851
pubmed:author
pubmed:issnType
Print
pubmed:day
28
pubmed:volume
117
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
91-102
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:11551635-Alleles, pubmed-meshheading:11551635-Amino Acid Substitution, pubmed-meshheading:11551635-Animals, pubmed-meshheading:11551635-Antimalarials, pubmed-meshheading:11551635-Drug Resistance, pubmed-meshheading:11551635-Genes, Protozoan, pubmed-meshheading:11551635-Inhibitory Concentration 50, pubmed-meshheading:11551635-Models, Molecular, pubmed-meshheading:11551635-Molecular Sequence Data, pubmed-meshheading:11551635-Parasitic Sensitivity Tests, pubmed-meshheading:11551635-Plasmodium falciparum, pubmed-meshheading:11551635-Proguanil, pubmed-meshheading:11551635-Protein Conformation, pubmed-meshheading:11551635-Pyrimethamine, pubmed-meshheading:11551635-Saccharomyces cerevisiae, pubmed-meshheading:11551635-Sequence Analysis, DNA, pubmed-meshheading:11551635-Tetrahydrofolate Dehydrogenase, pubmed-meshheading:11551635-Triazines
pubmed:year
2001
pubmed:articleTitle
Novel alleles of the Plasmodium falciparum dhfr highly resistant to pyrimethamine and chlorcycloguanil, but not WR99210.
pubmed:affiliation
Department of Genetics, University of Washington, Seattle, WA 98195-7360, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't