Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains

The increasing ineffectiveness of traditional antibiotics and the rise of multidrug resistant (MDR) bacteria have necessitated the revival of bacteriophage (phage) therapy. However, bacteria might also evolve resistance against phages. Phages and their bacterial hosts coexist in nature, resulting in...

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Autores principales:	Sarshad Koderi Valappil, Prateek Shetty, Zoltán Deim, Gabriella Terhes, Edit Urbán, Sándor Váczi, Roland Patai, Tamás Polgár, Botond Zsombor Pertics, György Schneider, Tamás Kovács, Gábor Rákhely
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	bacteriophage therapy combined treatment phage resistance phage-provoked sequential genomic mutation/deletion MexXY-OprM efflux system Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/972bd7a2e05c463dbeb7a8f041c1776c
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spelling	oai:doaj.org-article:972bd7a2e05c463dbeb7a8f041c1776c2021-12-02T11:40:46ZSurvival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains1664-302X10.3389/fmicb.2021.783722https://doaj.org/article/972bd7a2e05c463dbeb7a8f041c1776c2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmicb.2021.783722/fullhttps://doaj.org/toc/1664-302XThe increasing ineffectiveness of traditional antibiotics and the rise of multidrug resistant (MDR) bacteria have necessitated the revival of bacteriophage (phage) therapy. However, bacteria might also evolve resistance against phages. Phages and their bacterial hosts coexist in nature, resulting in a continuous coevolutionary competition for survival. We have isolated several clinical strains of Pseudomonas aeruginosa and phages that infect them. Among these, the PIAS (Phage Induced Antibiotic Sensitivity) phage belonging to the Myoviridae family can induce multistep genomic deletion in drug-resistant clinical strains of P. aeruginosa, producing a compromised drug efflux system in the bacterial host. We identified two types of mutant lines in the process: green mutants with SNPs (single nucleotide polymorphisms) and smaller deletions and brown mutants with large (∼250 kbp) genomic deletion. We demonstrated that PIAS used the MexXY-OprM system to initiate the infection. P. aeruginosa clogged PIAS phage infection by either modifying or deleting these receptors. The green mutant gaining phage resistance by SNPs could be overcome by evolved PIASs (E-PIASs) with a mutation in its tail-fiber protein. Characterization of the mutant phages will provide a deeper understanding of phage-host interaction. The coevolutionary process continued with large deletions in the same regions of the bacterial genomes to block the (E-)PIAS infection. These mutants gained phage resistance via either complete loss or substantial modifications of the phage receptor, MexXY-OprM, negating its essential role in antibiotic resistance. In vitro and in vivo studies indicated that combined use of PIAS and antibiotics could effectively inhibit P. aeruginosa growth. The phage can either eradicate bacteria or induce antibiotic sensitivity in MDR-resistant clinical strains. We have explored the potential use of combination therapy as an alternative approach against MDR P. aeruginosa infection.Sarshad Koderi ValappilPrateek ShettyPrateek ShettyZoltán DeimGabriella TerhesEdit UrbánSándor VácziRoland PataiTamás PolgárTamás PolgárBotond Zsombor PerticsGyörgy SchneiderTamás KovácsTamás KovácsGábor RákhelyGábor RákhelyFrontiers Media S.A.articlebacteriophage therapycombined treatmentphage resistancephage-provoked sequential genomic mutation/deletionMexXY-OprM efflux systemMicrobiologyQR1-502ENFrontiers in Microbiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	bacteriophage therapy combined treatment phage resistance phage-provoked sequential genomic mutation/deletion MexXY-OprM efflux system Microbiology QR1-502
spellingShingle	bacteriophage therapy combined treatment phage resistance phage-provoked sequential genomic mutation/deletion MexXY-OprM efflux system Microbiology QR1-502 Sarshad Koderi Valappil Prateek Shetty Prateek Shetty Zoltán Deim Gabriella Terhes Edit Urbán Sándor Váczi Roland Patai Tamás Polgár Tamás Polgár Botond Zsombor Pertics György Schneider Tamás Kovács Tamás Kovács Gábor Rákhely Gábor Rákhely Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains
description	The increasing ineffectiveness of traditional antibiotics and the rise of multidrug resistant (MDR) bacteria have necessitated the revival of bacteriophage (phage) therapy. However, bacteria might also evolve resistance against phages. Phages and their bacterial hosts coexist in nature, resulting in a continuous coevolutionary competition for survival. We have isolated several clinical strains of Pseudomonas aeruginosa and phages that infect them. Among these, the PIAS (Phage Induced Antibiotic Sensitivity) phage belonging to the Myoviridae family can induce multistep genomic deletion in drug-resistant clinical strains of P. aeruginosa, producing a compromised drug efflux system in the bacterial host. We identified two types of mutant lines in the process: green mutants with SNPs (single nucleotide polymorphisms) and smaller deletions and brown mutants with large (∼250 kbp) genomic deletion. We demonstrated that PIAS used the MexXY-OprM system to initiate the infection. P. aeruginosa clogged PIAS phage infection by either modifying or deleting these receptors. The green mutant gaining phage resistance by SNPs could be overcome by evolved PIASs (E-PIASs) with a mutation in its tail-fiber protein. Characterization of the mutant phages will provide a deeper understanding of phage-host interaction. The coevolutionary process continued with large deletions in the same regions of the bacterial genomes to block the (E-)PIAS infection. These mutants gained phage resistance via either complete loss or substantial modifications of the phage receptor, MexXY-OprM, negating its essential role in antibiotic resistance. In vitro and in vivo studies indicated that combined use of PIAS and antibiotics could effectively inhibit P. aeruginosa growth. The phage can either eradicate bacteria or induce antibiotic sensitivity in MDR-resistant clinical strains. We have explored the potential use of combination therapy as an alternative approach against MDR P. aeruginosa infection.
format	article
author	Sarshad Koderi Valappil Prateek Shetty Prateek Shetty Zoltán Deim Gabriella Terhes Edit Urbán Sándor Váczi Roland Patai Tamás Polgár Tamás Polgár Botond Zsombor Pertics György Schneider Tamás Kovács Tamás Kovács Gábor Rákhely Gábor Rákhely
author_facet	Sarshad Koderi Valappil Prateek Shetty Prateek Shetty Zoltán Deim Gabriella Terhes Edit Urbán Sándor Váczi Roland Patai Tamás Polgár Tamás Polgár Botond Zsombor Pertics György Schneider Tamás Kovács Tamás Kovács Gábor Rákhely Gábor Rákhely
author_sort	Sarshad Koderi Valappil
title	Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains
title_short	Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains
title_full	Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains
title_fullStr	Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains
title_full_unstemmed	Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains
title_sort	survival comes at a cost: a coevolution of phage and its host leads to phage resistance and antibiotic sensitivity of pseudomonas aeruginosa multidrug resistant strains
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/972bd7a2e05c463dbeb7a8f041c1776c
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Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains

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