Document Detail

Structural engineering of a phage lysin that targets gram-negative pathogens.
MedLine Citation:
PMID:  22679291     Owner:  NLM     Status:  MEDLINE    
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.
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:
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:
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:
Created Date:  2012-06-20     Completed Date:  2012-09-10     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9857-62     Citation Subset:  IM    
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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MeSH Terms
Bacterial Proteins / 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
Reg. No./Substance:
0/Bacterial Proteins; 0/Bacteriocins; 0/FyuA protein, Yersinia; 0/Mucoproteins; 0/Receptors, Cell Surface; 0/lysin; 37203-44-4/Pesticin
Comment In:
Virulence. 2013 Jan 1;4(1):90-1   [PMID:  23314572 ]
Nat Rev Microbiol. 2012 Aug;10(8):520-1   [PMID:  22728586 ]

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