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Lytic bacteriophages facilitate antibiotic sensitization of Enterococcus faecium

Gregory S. Canfield, Anushila Chatterjee, Juliel Espinosa, Mihnea R. Mangalea, Emma K. Sheriff, Micah Keidan, Sara W. McBride, Bruce D. McCollister, Howard C. Hang, View ORCID ProfileBreck A. Duerkop
doi: https://doi.org/10.1101/2020.09.22.309401
Gregory S. Canfield
aDivision of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
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Anushila Chatterjee
bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
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Juliel Espinosa
cLaboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York, USA
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Mihnea R. Mangalea
bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
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Emma K. Sheriff
bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
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Micah Keidan
bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
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Sara W. McBride
bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
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Bruce D. McCollister
aDivision of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
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Howard C. Hang
cLaboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York, USA
dDepartments of Immunology & Microbiology and Chemistry, Scripps Research, La Jolla, California, USA
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Breck A. Duerkop
bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
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  • ORCID record for Breck A. Duerkop
  • For correspondence: breck.duerkop@cuanschutz.edu
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Abstract

Enterococcus faecium, a commensal of the human intestine, has emerged as a hospital-adapted, multi-drug resistant (MDR) pathogen. Bacteriophages (phages), natural predators of bacteria, have regained attention as therapeutics to stem the rise of MDR bacteria. Despite their potential to curtail MDR E. faecium infections, the molecular events governing E. faecium-phage interactions remain largely unknown. Such interactions are important to delineate because phage selective pressure imposed on E. faecium will undoubtedly result in phage resistance phenotypes that could threaten the efficacy of phage therapy. In an effort to understand the emergence of phage resistance in E. faecium, three newly isolated lytic phages were used to demonstrate that E. faecium phage resistance is conferred through an array of cell wall-associated molecules, including secreted antigen A (SagA), enterococcal polysaccharide antigen (Epa), wall teichoic acids, capsule, and an arginine-aspartate-aspartate (RDD) protein of unknown function. We find that capsule and Epa are important for robust phage adsorption and that phage resistance mutations in sagA, epaR, and epaX enhance E. faecium susceptibility to ceftriaxone, an antibiotic normally ineffective due to its low affinity for enterococcal penicillin binding proteins. Consistent with these findings, we provide evidence that phages potently synergize with cell wall (ceftriaxone and ampicillin) and membrane-acting (daptomycin) antimicrobials to slow or completely inhibit the growth of E. faecium. Our work demonstrates that the evolution of phage resistance comes with fitness defects resulting in drug sensitization and that lytic phages could potentially serve as antimicrobial adjuvants in treating E. faecium infections.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.ebi.ac.uk/ena/browser/view/PRJEB39873

  • https://www.ncbi.nlm.nih.gov/bioproject/?term=MT939240

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 27, 2021.
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Lytic bacteriophages facilitate antibiotic sensitization of Enterococcus faecium
Gregory S. Canfield, Anushila Chatterjee, Juliel Espinosa, Mihnea R. Mangalea, Emma K. Sheriff, Micah Keidan, Sara W. McBride, Bruce D. McCollister, Howard C. Hang, Breck A. Duerkop
bioRxiv 2020.09.22.309401; doi: https://doi.org/10.1101/2020.09.22.309401
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Lytic bacteriophages facilitate antibiotic sensitization of Enterococcus faecium
Gregory S. Canfield, Anushila Chatterjee, Juliel Espinosa, Mihnea R. Mangalea, Emma K. Sheriff, Micah Keidan, Sara W. McBride, Bruce D. McCollister, Howard C. Hang, Breck A. Duerkop
bioRxiv 2020.09.22.309401; doi: https://doi.org/10.1101/2020.09.22.309401

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