Use of a bacteriophage lysin to identify a novel target for antimicrobial development

We identified an essential cell wall biosynthetic enzyme in Bacillus anthracis and an inhibitor thereof to which the organism did not spontaneously evolve measurable resistance. This work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have e...

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Bibliographic Details
Published in:PloS one 2013-04, Vol.8 (4), p.e60754-e60754
Main Authors: Schuch, Raymond, Pelzek, Adam J, Raz, Assaf, Euler, Chad W, Ryan, Patricia A, Winer, Benjamin Y, Farnsworth, Andrew, Bhaskaran, Shyam S, Stebbins, C Erec, Xu, Yong, Clifford, Adrienne, Bearss, David J, Vankayalapati, Hariprasad, Goldberg, Allan R, Fischetti, Vincent A
Format: Article
Language:English
Subjects:
Animals
Anti-Infective Agents - pharmacology
Antibiotics
Antiinfectives and antibacterials
Antimicrobial agents
Bacillus anthracis
Bacillus anthracis - drug effects
Bacillus anthracis - growth & development
Bacteria
Bacteriology
Bacteriophages - metabolism
Biology
Cell walls
Coding
DNA Primers
Drug resistance
Enzymes
Epimerase
Evolution
Female
Immunology
Inhibitors
Kinases
Laboratories
Lysins
Medicine
Mice
Mice, Inbred C57BL
Microbial drug resistance
Microbial Sensitivity Tests
Mucoproteins - metabolism
Mutation
Pathogenesis
Phages
Pharmaceuticals
Polymerase Chain Reaction
Receptors
Target recognition
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Summary:We identified an essential cell wall biosynthetic enzyme in Bacillus anthracis and an inhibitor thereof to which the organism did not spontaneously evolve measurable resistance. This work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have evolved to recognize critical receptors within the bacterial cell wall. Focusing on the B. anthracis-specific PlyG lysin, we first identified its unique cell wall receptor and cognate biosynthetic pathway. Within this pathway, one biosynthetic enzyme, 2-epimerase, was required for both PlyG receptor expression and bacterial growth. The 2-epimerase was used to design a small-molecule inhibitor, epimerox. Epimerox prevented growth of several Gram-positive pathogens and rescued mice challenged with lethal doses of B. anthracis. Importantly, resistance to epimerox was not detected (
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0060754