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Inhibition of glutathione biosynthesis sensitizes Plasmodium berghei to antifolates
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Document Title
Inhibition of glutathione biosynthesis sensitizes Plasmodium berghei to antifolates
Author
Songsungthong W., Koonyosying P., Uthaipibull C., Kamchonwongpaisan S.
Name from Authors Collection
Affiliations
National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand
Type
Article
Source Title
Antimicrobial Agents and Chemotherapy
ISSN
00664804
Year
2016
Volume
60
Issue
5
Page
3057-3064
Open Access
All Open Access, Bronze, Green
Publisher
American Society for Microbiology
DOI
10.1128/AAC.01836-15
Format
Abstract
Glutathione plays a central role in maintaining cellular redox homeostasis, and modulations to this status may affect malaria parasite sensitivity to certain types of antimalarials. In this study, we demonstrate that inhibition of glutathione biosynthesis in the Plasmodium berghei ANKA strain through disruption of the γ-glutamylcysteine synthetase (γ-GCS) gene, which encodes the first and rate-limiting enzyme in the glutathione biosynthetic pathway, significantly sensitizes parasites in vivo to pyrimethamine and sulfadoxine, but not to chloroquine, artesunate, or primaquine, compared with control parasites containing the same pyrimethamine-resistant marker cassette. Treatment of mice infected with an antifolate-resistant P. berghei control line with a γ-GCS inhibitor, buthionine sulfoximine, could partially abrogate pyrimethamine and sulfadoxine resistance. The role of glutathione in modulating the malaria parasite's response to antifolates suggests that development of specific inhibitors against Plasmodium γ-GCS may offer a new approach to counter Plasmodium antifolate resistance. © Copyright 2016, American Society for Microbiology. All Rights Reserved.
Industrial Classification
Knowledge Taxonomy Level 1
Knowledge Taxonomy Level 2
Knowledge Taxonomy Level 3
Funding Sponsor
Howard Hughes Medical Institute; National Science and Technology Development Agency; National Center for Genetic Engineering and Biotechnology
License
N/A
Rights
N/A
Publication Source
Scopus