title: Inhibition of Glutathione Biosynthesis Sensitizes Plasmodium berghei to Antifolates.
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.
authors.affiliation: National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand warangkhana.son@biotec.or.th.
authors.forename: Warangkhana
authors.initials: W
authors.lastname: Songsungthong
authors.affiliation: National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
authors.forename: Pongpisid
authors.initials: P
authors.lastname: Koonyosying
authors.affiliation: National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
authors.forename: Chairat
authors.initials: C
authors.lastname: Uthaipibull
authors.affiliation: National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity*; D011739:Pyrimethamine / Q000494:pharmacology; D013413:Sulfadoxine / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D013413:Sulfadoxine; D002738:Chloroquine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D011739:Pyrimethamine