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Antimicrobial Agents and Chemotherapy, September 2006, p. 3132-3141, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00621-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Eosin B as a Novel Antimalarial Agent for Drug-Resistant Plasmodium falciparum{dagger}

Kristen M. Massimine,1,2 Michael T. McIntosh,2 Lanxuan T. Doan,1 Chloé E. Atreya,1 Stephan Gromer,3 Worachart Sirawaraporn,4 David A. Elliott,2,{ddagger} Keith A. Joiner,2,{ddagger} R. Heiner Schirmer,3 and Karen S. Anderson1*

Department of Pharmacology,1 Infectious Diseases Section, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520,2 Biochemistry Center, Im Neuenheimer Feld 504, Heidelberg University, D-69120, Heidelberg, Germany,3 Department of Biochemistry, Mahidol University, Bangkok, Thailand4

Received 19 May 2006/ Returned for modification 27 May 2006/ Accepted 10 June 2006

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 (IC50) of 180 µM. 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 IC50 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.

* Corresponding author. Mailing address: Yale University School of Medicine, SHM B350-B, 333 Cedar St., New Haven, CT 06520. Phone: (203) 785-4526. Fax: (203) 785-7670. E-mail: karen.anderson{at}yale.edu.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} Present address: Department of Cell Biology and Anatomy, University of Arizona Medical Center, Tucson, AZ 85724.

Antimicrobial Agents and Chemotherapy, September 2006, p. 3132-3141, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00621-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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