Molecular Basis for Lytic Bacteriophage Resistance in Enterococci

ABSTRACT The human intestine harbors diverse communities of bacteria and bacteriophages. Given the specificity of phages for their bacterial hosts, there is growing interest in using phage therapies to combat the rising incidence of multidrug-resistant bacterial infections. A significant barrier to...

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Autores principales:	Breck A. Duerkop, Wenwen Huo, Pooja Bhardwaj, Kelli L. Palmer, Lora V. Hooper
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/da554fd4d63c49bca75623e1ecb6509f
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spelling	oai:doaj.org-article:da554fd4d63c49bca75623e1ecb6509f2021-11-15T15:50:18ZMolecular Basis for Lytic Bacteriophage Resistance in Enterococci10.1128/mBio.01304-162150-7511https://doaj.org/article/da554fd4d63c49bca75623e1ecb6509f2016-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01304-16https://doaj.org/toc/2150-7511ABSTRACT The human intestine harbors diverse communities of bacteria and bacteriophages. Given the specificity of phages for their bacterial hosts, there is growing interest in using phage therapies to combat the rising incidence of multidrug-resistant bacterial infections. A significant barrier to such therapies is the rapid development of phage-resistant bacteria, highlighting the need to understand how bacteria acquire phage resistance in vivo. Here we identify novel lytic phages in municipal raw sewage that kill Enterococcus faecalis, a Gram-positive opportunistic pathogen that resides in the human intestine. We show that phage infection of E. faecalis requires a predicted integral membrane protein that we have named PIPEF (for phage infection protein from E. faecalis). We find that PIPEF is conserved in E. faecalis and harbors a 160-amino-acid hypervariable region that determines phage tropism for distinct enterococcal strains. Finally, we use a gnotobiotic mouse model of in vivo phage predation to show that the sewage phages temporarily reduce E. faecalis colonization of the intestine but that E. faecalis acquires phage resistance through mutations in PIPEF. Our findings define the molecular basis for an evolutionary arms race between E. faecalis and the lytic phages that prey on them. They also suggest approaches for engineering E. faecalis phages that have altered host specificity and that can subvert phage resistance in the host bacteria. IMPORTANCE Bacteriophage therapy has received renewed attention as a potential solution to the rise in antibiotic-resistant bacterial infections. However, bacteria can acquire phage resistance, posing a major barrier to phage therapy. To overcome this problem, it is necessary to understand phage resistance mechanisms in bacteria. We have unraveled one such resistance mechanism in Enterococcus faecalis, a Gram-positive natural resident of the human intestine that has acquired antibiotic resistance and can cause opportunistic infections. We have identified a cell wall protein hypervariable region that specifies phage tropism in E. faecalis. Using a gnotobiotic mouse model of in vivo phage predation, we show that E. faecalis acquires phage resistance through mutations in this cell wall protein. Our findings define the molecular basis for lytic phage resistance in E. faecalis. They also suggest opportunities for engineering E. faecalis phages that circumvent the problem of bacterial phage resistance.Breck A. DuerkopWenwen HuoPooja BhardwajKelli L. PalmerLora V. HooperAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Breck A. Duerkop Wenwen Huo Pooja Bhardwaj Kelli L. Palmer Lora V. Hooper Molecular Basis for Lytic Bacteriophage Resistance in Enterococci
description	ABSTRACT The human intestine harbors diverse communities of bacteria and bacteriophages. Given the specificity of phages for their bacterial hosts, there is growing interest in using phage therapies to combat the rising incidence of multidrug-resistant bacterial infections. A significant barrier to such therapies is the rapid development of phage-resistant bacteria, highlighting the need to understand how bacteria acquire phage resistance in vivo. Here we identify novel lytic phages in municipal raw sewage that kill Enterococcus faecalis, a Gram-positive opportunistic pathogen that resides in the human intestine. We show that phage infection of E. faecalis requires a predicted integral membrane protein that we have named PIPEF (for phage infection protein from E. faecalis). We find that PIPEF is conserved in E. faecalis and harbors a 160-amino-acid hypervariable region that determines phage tropism for distinct enterococcal strains. Finally, we use a gnotobiotic mouse model of in vivo phage predation to show that the sewage phages temporarily reduce E. faecalis colonization of the intestine but that E. faecalis acquires phage resistance through mutations in PIPEF. Our findings define the molecular basis for an evolutionary arms race between E. faecalis and the lytic phages that prey on them. They also suggest approaches for engineering E. faecalis phages that have altered host specificity and that can subvert phage resistance in the host bacteria. IMPORTANCE Bacteriophage therapy has received renewed attention as a potential solution to the rise in antibiotic-resistant bacterial infections. However, bacteria can acquire phage resistance, posing a major barrier to phage therapy. To overcome this problem, it is necessary to understand phage resistance mechanisms in bacteria. We have unraveled one such resistance mechanism in Enterococcus faecalis, a Gram-positive natural resident of the human intestine that has acquired antibiotic resistance and can cause opportunistic infections. We have identified a cell wall protein hypervariable region that specifies phage tropism in E. faecalis. Using a gnotobiotic mouse model of in vivo phage predation, we show that E. faecalis acquires phage resistance through mutations in this cell wall protein. Our findings define the molecular basis for lytic phage resistance in E. faecalis. They also suggest opportunities for engineering E. faecalis phages that circumvent the problem of bacterial phage resistance.
format	article
author	Breck A. Duerkop Wenwen Huo Pooja Bhardwaj Kelli L. Palmer Lora V. Hooper
author_facet	Breck A. Duerkop Wenwen Huo Pooja Bhardwaj Kelli L. Palmer Lora V. Hooper
author_sort	Breck A. Duerkop
title	Molecular Basis for Lytic Bacteriophage Resistance in Enterococci
title_short	Molecular Basis for Lytic Bacteriophage Resistance in Enterococci
title_full	Molecular Basis for Lytic Bacteriophage Resistance in Enterococci
title_fullStr	Molecular Basis for Lytic Bacteriophage Resistance in Enterococci
title_full_unstemmed	Molecular Basis for Lytic Bacteriophage Resistance in Enterococci
title_sort	molecular basis for lytic bacteriophage resistance in enterococci
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/da554fd4d63c49bca75623e1ecb6509f
work_keys_str_mv	AT breckaduerkop molecularbasisforlyticbacteriophageresistanceinenterococci AT wenwenhuo molecularbasisforlyticbacteriophageresistanceinenterococci AT poojabhardwaj molecularbasisforlyticbacteriophageresistanceinenterococci AT kellilpalmer molecularbasisforlyticbacteriophageresistanceinenterococci AT loravhooper molecularbasisforlyticbacteriophageresistanceinenterococci
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Molecular Basis for Lytic Bacteriophage Resistance in Enterococci

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