Natural Bred ε2-Phages Have an Improved Host Range and Virulence against Uropathogenic Escherichia coli over Their Ancestor Phages

Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 ...

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Autores principales:	Maria Loose, David Sáez Moreno, Michele Mutti, Eva Hitzenhammer, Zehra Visram, David Dippel, Susanne Schertler, Lenka Podpera Tišáková, Johannes Wittmann, Lorenzo Corsini, Florian Wagenlehner
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	phage therapy phage breeding <i>E. coli</i> urinary tract infections phage training homologous recombination Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ae8ac31bc865467e8a71d115bf0a1345
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spelling	oai:doaj.org-article:ae8ac31bc865467e8a71d115bf0a13452021-11-25T16:23:03ZNatural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages10.3390/antibiotics101113372079-6382https://doaj.org/article/ae8ac31bc865467e8a71d115bf0a13452021-11-01T00:00:00Zhttps://www.mdpi.com/2079-6382/10/11/1337https://doaj.org/toc/2079-6382Alternative treatments for <i>Escherichia coli</i> infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 <i>E. coli</i> strains reflecting the diversity of strains found in UTI, including sequence type 131, 73 and 69. The plaquing host range (PHR) was between 13 and 63%. In contrast, the kinetic host range (KHR), describing the percentage of strains for which growth in suspension was suppressed for 24 h, was between 0% and 19%, substantially lower than the PHR. To improve the phage host range and their efficacy, we bred the phages by mixing and propagating cocktails on a subset of <i>E. coli</i> strains. The bred phages, which we termed evolution-squared ε<sup>2</sup>-phages, of a mixture of <i>Myoviridae</i> have KHRs up to 23% broader compared to their ancestors. Furthermore, using constant phage concentrations, <i>Myoviridae</i> ε<sup>2</sup>-phages suppressed the growth of higher bacterial inocula than their ancestors did. Thus, the ε<sup>2</sup>-phages were more virulent compared to their ancestors. Analysis of the genetic sequences of the ε<sup>2</sup>-phages with the broadest host range reveals that they are mosaic intercrossings of 2–3 ancestor phages. The recombination sites are distributed over the whole length of the genome. All ε<sup>2</sup>-phages are devoid of genes conferring lysogeny, antibiotic resistance, or virulence. Overall, this study shows that ε<sup>2</sup>-phages are remarkably more suitable than the wild-type phages for phage therapy.Maria LooseDavid Sáez MorenoMichele MuttiEva HitzenhammerZehra VisramDavid DippelSusanne SchertlerLenka Podpera TišákováJohannes WittmannLorenzo CorsiniFlorian WagenlehnerMDPI AGarticlephage therapyphage breeding<i>E. coli</i>urinary tract infectionsphage traininghomologous recombinationTherapeutics. PharmacologyRM1-950ENAntibiotics, Vol 10, Iss 1337, p 1337 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	phage therapy phage breeding <i>E. coli</i> urinary tract infections phage training homologous recombination Therapeutics. Pharmacology RM1-950
spellingShingle	phage therapy phage breeding <i>E. coli</i> urinary tract infections phage training homologous recombination Therapeutics. Pharmacology RM1-950 Maria Loose David Sáez Moreno Michele Mutti Eva Hitzenhammer Zehra Visram David Dippel Susanne Schertler Lenka Podpera Tišáková Johannes Wittmann Lorenzo Corsini Florian Wagenlehner Natural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages
description	Alternative treatments for <i>Escherichia coli</i> infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 <i>E. coli</i> strains reflecting the diversity of strains found in UTI, including sequence type 131, 73 and 69. The plaquing host range (PHR) was between 13 and 63%. In contrast, the kinetic host range (KHR), describing the percentage of strains for which growth in suspension was suppressed for 24 h, was between 0% and 19%, substantially lower than the PHR. To improve the phage host range and their efficacy, we bred the phages by mixing and propagating cocktails on a subset of <i>E. coli</i> strains. The bred phages, which we termed evolution-squared ε<sup>2</sup>-phages, of a mixture of <i>Myoviridae</i> have KHRs up to 23% broader compared to their ancestors. Furthermore, using constant phage concentrations, <i>Myoviridae</i> ε<sup>2</sup>-phages suppressed the growth of higher bacterial inocula than their ancestors did. Thus, the ε<sup>2</sup>-phages were more virulent compared to their ancestors. Analysis of the genetic sequences of the ε<sup>2</sup>-phages with the broadest host range reveals that they are mosaic intercrossings of 2–3 ancestor phages. The recombination sites are distributed over the whole length of the genome. All ε<sup>2</sup>-phages are devoid of genes conferring lysogeny, antibiotic resistance, or virulence. Overall, this study shows that ε<sup>2</sup>-phages are remarkably more suitable than the wild-type phages for phage therapy.
format	article
author	Maria Loose David Sáez Moreno Michele Mutti Eva Hitzenhammer Zehra Visram David Dippel Susanne Schertler Lenka Podpera Tišáková Johannes Wittmann Lorenzo Corsini Florian Wagenlehner
author_facet	Maria Loose David Sáez Moreno Michele Mutti Eva Hitzenhammer Zehra Visram David Dippel Susanne Schertler Lenka Podpera Tišáková Johannes Wittmann Lorenzo Corsini Florian Wagenlehner
author_sort	Maria Loose
title	Natural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages
title_short	Natural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages
title_full	Natural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages
title_fullStr	Natural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages
title_full_unstemmed	Natural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages
title_sort	natural bred ε<sup>2</sup>-phages have an improved host range and virulence against uropathogenic <i>escherichia coli</i> over their ancestor phages
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ae8ac31bc865467e8a71d115bf0a1345
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Natural Bred ε<sup>2</sup>-Phages Have an Improved Host Range and Virulence against Uropathogenic <i>Escherichia coli</i> over Their Ancestor Phages

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