| Structural engineering of a phage lysin that targets gram-negative pathogens. | |
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MedLine Citation:
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PMID: 22679291 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Bacterial pathogens are becoming increasingly resistant to antibiotics. As an alternative therapeutic strategy, phage therapy reagents containing purified viral lysins have been developed against gram-positive organisms but not against gram-negative organisms due to the inability of these types of drugs to cross the bacterial outer membrane. We solved the crystal structures of a Yersinia pestis outer membrane transporter called FyuA and a bacterial toxin called pesticin that targets this transporter. FyuA is a β-barrel membrane protein belonging to the family of TonB dependent transporters, whereas pesticin is a soluble protein with two domains, one that binds to FyuA and another that is structurally similar to phage T4 lysozyme. The structure of pesticin allowed us to design a phage therapy reagent comprised of the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme. This hybrid toxin kills specific Yersinia and pathogenic E. coli strains and, importantly, can evade the pesticin immunity protein (Pim) giving it a distinct advantage over pesticin. Furthermore, because FyuA is required for virulence and is more common in pathogenic bacteria, the hybrid toxin also has the advantage of targeting primarily disease-causing bacteria rather than indiscriminately eliminating natural gut flora. |
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Authors:
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Petra Lukacik; Travis J Barnard; Paul W Keller; Kaveri S Chaturvedi; Nadir Seddiki; James W Fairman; Nicholas Noinaj; Tara L Kirby; Jeffrey P Henderson; Alasdair C Steven; B Joseph Hinnebusch; Susan K Buchanan |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-06-07 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 109 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-06-20 Completed Date: 2012-09-10 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 9857-62 Citation Subset: IM |
Affiliation:
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Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Bacterial Proteins
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chemistry Bacteriocins / chemistry Bacteriophages / metabolism*, physiology Cell Membrane / metabolism Cryoelectron Microscopy Gram-Negative Bacteria / virology* Models, Molecular Mucoproteins / chemistry, metabolism* Protein Conformation Protein Engineering Protein Transport Receptors, Cell Surface / chemistry |
| Grant Support | |
ID/Acronym/Agency:
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K12 HD001459-09/HD/NICHD NIH HHS; P50 DK064540/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bacterial Proteins; 0/Bacteriocins; 0/FyuA protein, Yersinia; 0/Mucoproteins; 0/Receptors, Cell Surface; 0/lysin; 37203-44-4/Pesticin |
| Comments/Corrections | |
Comment In:
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Nat Rev Microbiol. 2012 Aug;10(8):520-1
[PMID:
22728586
]
Virulence. 2013 Jan 1;4(1):90-1 [PMID: 23314572 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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