Eosin B as a novel antimalarial agent for drug-resistant Plasmodium falciparum.
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.
Massimine
Kristen M
KM
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
McIntosh
Michael T
MT
Doan
Lanxuan T
LT
Atreya
Chloé E
CE
Gromer
Stephan
S
Sirawaraporn
Worachart
W
Elliott
David A
DA
Joiner
Keith A
KA
Schirmer
R Heiner
RH
Anderson
Karen S
KS
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
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