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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Roberts, C. W. Samuel, B. U. Wernimont, S. Mack, D. Rothbard, J. Rice, D. W. Muench, S. P. Mcleod, R. Prigge, S. T. Law, A. B. Wender, P. Mui, E. Hearn, B. Kirisits, M. J. |
| Description | Author Affiliation: Samuel BU ( Department of Visual Sciences, University of Chicago, 5841 South Maryland, AMB S-208, Chicago, IL 60637, USA.); |
| Abstract | To eliminate apicomplexan parasites, inhibitory compounds must cross host cell, parasitophorous vacuole, and parasite membranes and cyst walls, making delivery challenging. Here, we show that short oligomers of arginine enter Toxoplasma gondii tachyzoites and encysted bradyzoites. Triclosan, which inhibits enoyl-ACP reductase (ENR), conjugated to arginine oligomers enters extracellular tachyzoites, host cells, tachyzoites inside parasitophorous vacuoles within host cells, extracellular bradyzoites, and bradyzoites within cysts. We identify, clone, and sequence T. gondii enr and produce and characterize enzymatically active, recombinant ENR. This enzyme has the requisite amino acids to bind triclosan. Triclosan released after conjugation to octaarginine via a readily hydrolyzable ester linkage inhibits ENR activity, tachyzoites in vitro, and tachyzoites in mice. Delivery of an inhibitor to a microorganism via conjugation to octaarginine provides an approach to transporting antimicrobials and other small molecules to sequestered parasites, a model system to characterize transport across multiple membrane barriers and structures, a widely applicable paradigm for treatment of active and encysted apicomplexan and other infections, and a generic proof of principle for a mechanism of medicine delivery. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 24 |
| Volume Number | 100 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2003-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Coccidiostats Administration & Dosage Toxoplasma Drug Effects Amino Acid Sequence Animals DNA, Protozoan Genetics Drug Delivery Systems Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) Enzyme Inhibitors Pharmacology Genes, Protozoan Mice Molecular Sequence Data Oxidoreductases Antagonists & Inhibitors Recombinant Proteins Sequence Homology, Amino Acid Enzymology Toxoplasmosis Drug Therapy Parasitology Triclosan Analogs & Derivatives Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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