Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum
- Author(s)
- Triglia, T; Menting, JGT; Wilson, C; Cowman, AF;
- Details
- Publication Year 1997-12-09,Volume 94,Issue #25,Page 13944-13949
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Publication Type
- Journal Article
- Abstract
- Plasmodium falciparum causes the most severe form of malaria in humans. An important class of drugs in malaria treatment is the sulfone/sulfonamide group, of which sulfadoxine is the most commonly used, The target of sulfadoxine is the enzyme dihydropteroate synthase (DHPS), and sequencing of the DHPS gene has identified amino acid differences that may be involved in the mechanism of resistance to this drug. In this study we have sequenced the DHPS gene in 10 isolates from Thailand and identified a new allele of DHPS that has a previously unidentified amino acid difference. We have expressed eight alleles of P. falciparum PPPK-DHPS in Escherichia coli and purified the functional enzymes to homogeneity. Strikingly the K-i for sulfadoxine varies by almost three orders of magnitude from 0.14 mu M for the DHPS allele from sensitive isolates to 112 mu M for an enzyme expressed in a highly resistant isolate. Comparison of the K-i of different sulfonamides and the sulfone dapsone has suggested that the amino acid differences in DHPS would confer cross-resistance to these compounds, These results show that the amino acid differences in the DHPS enzyme of sulfadoxine-resistant isolates of P. falciparum are central to the mechanism of resistance to sulfones and sulfonamides,
- Publisher
- NATL ACAD SCIENCES
- Keywords
- HUMAN MALARIA PARASITE; DIHYDROFOLATE-REDUCTASE; HYDROXYMETHYLDIHYDROPTERIN PYROPHOSPHOKINASE; PYRIMETHAMINE RESISTANCE; ANTIMALARIAL ACTIVITY; FOLIC-ACID; GENE; SULFADOXINE; EXPRESSION; INVITRO
- Publisher's Version
- https://doi.org/10.1073/pnas.94.25.13944
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 1997-12-09 12:00:00