title: Eosin B as a novel antimalarial agent for drug-resistant Plasmodium falciparum.
abstract: 4',5'-Dibromo-2',7'-dinitrofluorescein, a red dye commonly referred to as eosin B, inhibits Toxoplasma gondii in both enzymatic and cell culture studies with a 50% inhibitory concentration (IC(50)) of 180 microM. As a non-active-site inhibitor of the bifunctional T. gondii dihydrofolate reductase-thymidylate synthase (DHFR-TS), eosin B offers a novel mechanism for inhibition of the parasitic folate biosynthesis pathway. In the present study, eosin B was further evaluated as a potential antiparasitic compound through in vitro and cell culture testing of its effects on Plasmodium falciparum. Our data revealed that eosin B is a highly selective, potent inhibitor of a variety of drug-resistant malarial strains, with an average IC(50) of 124 nM. Furthermore, there is no indication of cross-resistance with other clinically utilized compounds, suggesting that eosin B is acting via a novel mechanism. The antimalarial mode of action appears to be multifaceted and includes extensive damage to membranes, the alteration of intracellular organelles, and enzymatic inhibition not only of DHFR-TS but also of glutathione reductase and thioredoxin reductase. In addition, preliminary studies suggest that eosin B is also acting as a redox cycling compound. Overall, our data suggest that eosin B is an effective lead compound for the development of new, more effective antimalarial drugs.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Massimine
authors.forename: Michael T
authors.initials: MT
authors.lastname: McIntosh
authors.forename: Lanxuan T
authors.initials: LT
authors.lastname: Doan
authors.forename: Chloé E
authors.initials: CE
authors.lastname: Atreya
authors.forename: Stephan
authors.initials: S
authors.lastname: Gromer
authors.forename: Worachart
authors.initials: W
authors.lastname: Sirawaraporn
authors.forename: David A
authors.initials: DA
authors.lastname: Elliott
authors.forename: Keith A
authors.initials: KA
authors.lastname: Joiner
authors.forename: R Heiner
authors.initials: RH
authors.lastname: Schirmer
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004351:Drug Resistance; D010697:Eosine I Bluish; D005347:Fibroblasts / Q000469:parasitology; D005452:Fluoresceins / Q000493:pharmacokinetics / Q000494:pharmacology*; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000962:Antimalarials; D005452:Fluoresceins; D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D013940:Thymidylate Synthase; D010697:Eosine I Bluish