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Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection

Schmelcher, Mathias ; Shen, Yang ; Nelson, Daniel C. ; Eugster, Marcel R. ; Eichenseher, Fritz ; Hanke, Daniela C. ; Loessner, Martin J. ; Dong, Shengli ; Pritchard, David G. ; Lee, Jean C. ; Becker, Stephen C. ; Foster-Frey, Juli ; Donovan, David M.

In: Journal of Antimicrobial Chemotherapy, 2015, vol. 70, no. 5, p. 1453-1465

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    Title
    • Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection
    Author
    • Schmelcher, Mathias. Animal Biosciences and Biotechnology Laboratory, ANRI, NEA, ARS, USDA, 10300 Baltimore Ave., Beltsville, MD 20705-2350, USA
    • Shen, Yang. Institute of Food, Nutrition and Health, ETH Zurich, Schmelzbergstrasse 7, 8092 Zurich, Switzerland
    • Nelson, Daniel C.. Institute for Bioscience and Biotechnology Research, University of Maryland, 9600 Gudelsky Drive, Rockville, MD 20850, USA
    • Eugster, Marcel R.. Institute of Food, Nutrition and Health, ETH Zurich, Schmelzbergstrasse 7, 8092 Zurich, Switzerland
    • Eichenseher, Fritz. Institute of Food, Nutrition and Health, ETH Zurich, Schmelzbergstrasse 7, 8092 Zurich, Switzerland
    • Hanke, Daniela C.. Institute of Food, Nutrition and Health, ETH Zurich, Schmelzbergstrasse 7, 8092 Zurich, Switzerland
    • Loessner, Martin J.. Institute of Food, Nutrition and Health, ETH Zurich, Schmelzbergstrasse 7, 8092 Zurich, Switzerland
    • Dong, Shengli. Department of Biochemistry and Molecular Genetics, MCLM 552, University of Alabama at Birmingham, 1530 3rd Ave., Birmingham, AL 35294-0005, USA
    • Pritchard, David G.. Department of Biochemistry and Molecular Genetics, MCLM 552, University of Alabama at Birmingham, 1530 3rd Ave., Birmingham, AL 35294-0005, USA
    • Lee, Jean C.. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
    • Becker, Stephen C.. Animal Biosciences and Biotechnology Laboratory, ANRI, NEA, ARS, USDA, 10300 Baltimore Ave., Beltsville, MD 20705-2350, USA
    • Foster-Frey, Juli. Animal Biosciences and Biotechnology Laboratory, ANRI, NEA, ARS, USDA, 10300 Baltimore Ave., Beltsville, MD 20705-2350, USA
    • Donovan, David M.. Animal Biosciences and Biotechnology Laboratory, ANRI, NEA, ARS, USDA, 10300 Baltimore Ave., Beltsville, MD 20705-2350, USA
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Journal of Antimicrobial Chemotherapy, 2015, vol. 70, no. 5, p. 1453-1465. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:304624
    Summary
    Objectives In the light of increasing drug resistance in Staphylococcus aureus, bacteriophage endolysins [peptidoglycan hydrolases (PGHs)] have been suggested as promising antimicrobial agents. The aim of this study was to determine the antimicrobial activity of nine enzymes representing unique homology groups within a diverse class of staphylococcal PGHs. Methods PGHs were recombinantly expressed, purified and tested for staphylolytic activity in multiple in vitro assays (zymogram, turbidity reduction assay and plate lysis) and against a comprehensive set of strains (S. aureus and CoNS). PGH cut sites in the staphylococcal peptidoglycan were determined by biochemical assays (Park-Johnson and Ghuysen procedures) and MS analysis. The enzymes were tested for their ability to eradicate static S. aureus biofilms and compared for their efficacy against systemic MRSA infection in a mouse model. Results Despite similar modular architectures and unexpectedly conserved cleavage sites in the peptidoglycan (conferred by evolutionarily divergent catalytic domains), the enzymes displayed varying degrees of in vitro lytic activity against numerous staphylococcal strains, including cell surface mutants and drug-resistant strains, and proved effective against static biofilms. In a mouse model of systemic MRSA infection, six PGHs provided 100% protection from death, with animals being free of clinical signs at the end of the experiment. Conclusions Our results corroborate the high potential of PGHs for treatment of S. aureus infections and reveal unique antimicrobial and biochemical properties of the different enzymes, suggesting a high diversity of potential applications despite highly conserved peptidoglycan target sites