title: Use of a bacteriophage lysin to identify a novel target for antimicrobial development.
abstract: 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 (<10(-11) frequency) in B. anthracis and S. aureus. These results describe the use of phage lysins to identify promising lead molecules with reduced resistance potential for antimicrobial development.
authors.affiliation: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, United States of America. rschuch@contrafect.com
authors.forename: Raymond
authors.initials: R
authors.lastname: Schuch
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Pelzek
authors.forename: Assaf
authors.initials: A
authors.lastname: Raz
authors.forename: Chad W
authors.initials: CW
authors.lastname: Euler
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ryan
authors.forename: Benjamin Y
authors.initials: BY
authors.lastname: Winer
authors.forename: Andrew
authors.initials: A
authors.lastname: Farnsworth
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Bhaskaran
authors.forename: C Erec
authors.initials: CE
authors.lastname: Stebbins
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Adrienne
authors.initials: A
authors.lastname: Clifford
authors.forename: David J
authors.initials: DJ
authors.lastname: Bearss
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: Allan R
authors.initials: AR
authors.lastname: Goldberg
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Fischetti
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects / Q000254:growth & development; D001435:Bacteriophages / Q000378:metabolism*; D017931:DNA Primers; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009088:Mucoproteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction
chemical_list: D000890:Anti-Infective Agents; D017931:DNA Primers; D009088:Mucoproteins; C010393:lysin, gastropoda