Document Detail


Small molecule perimeter defense in entomopathogenic bacteria.
MedLine Citation:
PMID:  22711807     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Two gram-negative insect pathogens, Xenorhabdus nematophila and Photorhabdus luminescens, produce rhabduscin, an amidoglycosyl- and vinyl-isonitrile-functionalized tyrosine derivative. Heterologous expression of the rhabduscin pathway in Escherichia coli, precursor-directed biosynthesis of rhabduscin analogs, biochemical assays, and visualization using both stimulated Raman scattering and confocal fluorescence microscopy established rhabduscin's role as a potent nanomolar-level inhibitor of phenoloxidase, a key component of the insect's innate immune system, as well as rhabduscin's localization at the bacterial cell surface. Stimulated Raman scattering microscopy visualized rhabduscin at the periphery of wild-type X. nematophila cells and E. coli cells heterologously expressing the rhabduscin pathway. Precursor-directed biosynthesis created rhabduscin mimics in X. nematophila pathway mutants that could be accessed at the bacterial cell surface by an extracellular bioorthogonal probe, as judged by confocal fluorescence microscopy. Biochemical assays using both wild-type and mutant X. nematophila cells showed that rhabduscin was necessary and sufficient for potent inhibition (low nM) of phenoloxidases, the enzymes responsible for producing melanin (the hard black polymer insects generate to seal off microbial pathogens). These observations suggest a model in which rhabduscin's physical association at the bacterial cell surface provides a highly effective inhibitor concentration directly at the site of phenoloxidase contact. This class of molecules is not limited to insect pathogens, as the human pathogen Vibrio cholerae also encodes rhabduscin's aglycone, and bacterial cell-coated immunosuppressants could be a general strategy to combat host defenses.
Authors:
Jason M Crawford; Cyril Portmann; Xu Zhang; Maarten B J Roeffaers; Jon Clardy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-18
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 Jul 
Date Detail:
Created Date:  2012-07-04     Completed Date:  2012-09-18     Revised Date:  2014-01-16    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10821-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Agaricales / enzymology
Animals
Bacterial Proteins / genetics,  metabolism
Gram-Negative Bacterial Infections / immunology,  metabolism,  microbiology
Hemolymph / metabolism
Humans
Immunity, Innate / physiology
Larva / growth & development,  immunology,  microbiology
Monophenol Monooxygenase / antagonists & inhibitors,  metabolism
Moths / growth & development,  immunology,  microbiology*
Mutagenesis / physiology
Photorhabdus / genetics,  immunology,  metabolism*
Spectrum Analysis, Raman
Vibrio cholerae / genetics,  immunology,  metabolism
Virulence Factors / genetics,  metabolism*
Xenorhabdus / genetics,  immunology,  metabolism*
Grant Support
ID/Acronym/Agency:
1K99 GM097096-01/GM/NIGMS NIH HHS; R00 GM097096/GM/NIGMS NIH HHS; R01 GM086258/GM/NIGMS NIH HHS; R01 GM086258/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Bacterial Proteins; 0/Virulence Factors; EC 1.14.18.1/Monophenol Monooxygenase
Comments/Corrections

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