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Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci

Anushila Chatterjee, Cydney N. Johnson, Phat Luong, Karthik Hullahalli, Sara W. McBride, Alyxandria M. Schubert, View ORCID ProfileKelli L. Palmer, Paul E. Carlson Jr, View ORCID ProfileBreck A. Duerkop
doi: https://doi.org/10.1101/531442
Anushila Chatterjee
aDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA, 80045.
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Cydney N. Johnson
aDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA, 80045.
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Phat Luong
aDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA, 80045.
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Karthik Hullahalli
bDepartment of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA, 75080.
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Sara W. McBride
aDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA, 80045.
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Alyxandria M. Schubert
cDivision of Bacterial, Parasitic, and Allergenic Products, Office of Vaccines Research and Review, Center for Biologics Evaluations and Research, Food and Drug Administration, Silver Spring, MD, USA, 20993.
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Kelli L. Palmer
bDepartment of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA, 75080.
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Paul E. Carlson Jr
cDivision of Bacterial, Parasitic, and Allergenic Products, Office of Vaccines Research and Review, Center for Biologics Evaluations and Research, Food and Drug Administration, Silver Spring, MD, USA, 20993.
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Breck A. Duerkop
aDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA, 80045.
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  • ORCID record for Breck A. Duerkop
  • For correspondence: breck.duerkop@ucdenver.edu
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Abstract

Enterococcus faecalis is a human intestinal pathobiont with intrinsic and acquired resistance to many antibiotics, including vancomycin. Nature provides a diverse and virtually untapped repertoire of bacterial viruses, or bacteriophages (phages), that could be harnessed to combat multi-drug resistant enterococcal infections. Bacterial phage resistance represents a potential barrier to the implementation of phage therapy, emphasizing the importance of investigating the molecular mechanisms underlying the emergence of phage resistance. Using a cohort of 19 environmental lytic phages with tropism against E. faecalis, we found that these phages require the enterococcal polysaccharide antigen (Epa) for productive infection. Epa is a surface-exposed heteroglycan synthesized by enzymes encoded by both conserved and strain specific genes. We discovered that exposure to phage selective pressure favors mutation in non-conserved epa genes both in culture and in a mouse model of intestinal colonization. Despite gaining phage resistance, epa mutant strains exhibited a loss of resistance to the cell wall targeting antibiotics, vancomycin and daptomycin. Finally, we show that an E. faecalis epa mutant strain is deficient in intestinal colonization, cannot expand its population upon antibiotic-driven intestinal dysbiosis and fails to be efficiently transmitted to juvenile mice following birth. This study demonstrates that phage therapy could be used in combination with antibiotics to target enterococci within a dysbiotic microbiota. Enterococci that evade phage therapy by developing resistance may be less fit at colonizing the intestine and sensitized to vancomycin preventing their overgrowth during antibiotic treatment.

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Posted January 26, 2019.
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Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci
Anushila Chatterjee, Cydney N. Johnson, Phat Luong, Karthik Hullahalli, Sara W. McBride, Alyxandria M. Schubert, Kelli L. Palmer, Paul E. Carlson Jr, Breck A. Duerkop
bioRxiv 531442; doi: https://doi.org/10.1101/531442
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Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci
Anushila Chatterjee, Cydney N. Johnson, Phat Luong, Karthik Hullahalli, Sara W. McBride, Alyxandria M. Schubert, Kelli L. Palmer, Paul E. Carlson Jr, Breck A. Duerkop
bioRxiv 531442; doi: https://doi.org/10.1101/531442

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