Allelic exchange at the endogenous genomic locus in Plasmodium falciparum proves the role of dihydropteroate synthase in sulfadoxine-resistant malaria

We have exploited the recently developed ability to trans‐ fect the malaria parasite Plasmodium falciparum to investigate the role of polymorphisms in the enzyme dihydropteroate synthase (DHPS), identified in sulfadoxine‐resistant field isolates. By using a truncated form of the dhps gene, specific...

Full description

Saved in:
Bibliographic Details
Published inThe EMBO journal Vol. 17; no. 14; pp. 3807 - 3815
Main Authors Triglia, Tony, Wang, Ping, Sims, Paul F.G., Hyde, John E., Cowman, Alan F.
Format Journal Article
LanguageEnglish
Published Chichester, UK John Wiley & Sons, Ltd 15.07.1998
Nature Publishing Group UK
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary:We have exploited the recently developed ability to trans‐ fect the malaria parasite Plasmodium falciparum to investigate the role of polymorphisms in the enzyme dihydropteroate synthase (DHPS), identified in sulfadoxine‐resistant field isolates. By using a truncated form of the dhps gene, specific mutations were introduced into the endogenous gene by allelic replacement such that they were under the control of the endogenous promoter. Using this approach a series of mutant dhps alleles that mirror P.falciparum variants found in field isolates were found to confer different levels of sulfadoxine resistance. This analysis shows that alteration of Ala437 to Gly (A437G) confers on the parasite a 5‐fold increase in sulfadoxine resistance and addition of further mutations increases the level of resistance to 24‐fold above that seen for the transfectant expressing the wild‐type dhps allele. This indicates that resistance to high levels of sulfadoxine in P.falciparum has arisen by an accumulation of mutations and that Gly437 is a key residue, consistent with its occurrence in most dhps alleles from resistant isolates. These studies provide proof that the mechanism of resistance to sulfadoxine in P.falciparum involves mutations in the dhps gene and determines the relative contribution of these mutations to this phenotype.
Bibliography:ArticleID:EMBJ7591083
istex:36CB6284FA93BF41F8923517BD25B6C4D72E7408
ark:/67375/WNG-BMCKPB6F-D
ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ISSN:0261-4189
1460-2075
DOI:10.1093/emboj/17.14.3807