Eosin B as a Novel Antimalarial Agent for Drug-Resistant Plasmodium falciparum
| Autor: | Karen S. Anderson, R. Heiner Schirmer, Chloé E. Atreya, Worachart Sirawaraporn, Keith A. Joiner, Lanxuan T. Doan, Stephan Gromer, Michael T. McIntosh, Kristen M. Massimine, David A. Elliott |
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| Rok vydání: | 2006 |
| Předmět: |
Thioredoxin-Disulfide Reductase
Eosine I Bluish Antiparasitic medicine.drug_class Thioredoxin reductase Plasmodium falciparum Drug Resistance Cell Line Antimalarials chemistry.chemical_compound Multienzyme Complexes parasitic diseases medicine Animals Humans Pharmacology (medical) Antimalarial Agent Mode of action Mechanisms of Action: Physiological Effects Pharmacology biology Thymidylate Synthase Fibroblasts Fluoresceins biology.organism_classification In vitro Tetrahydrofolate Dehydrogenase Glutathione Reductase Infectious Diseases chemistry Biochemistry Cell culture Eosin B |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 50:3132-3141 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00621-06 |
| Popis: | 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 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 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. |
| Databáze: | OpenAIRE |
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