ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages

Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) compose...

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Published inPharmaceuticals (Basel, Switzerland) Vol. 14; no. 4; p. 325
Main Authors Sáez Moreno, David, Visram, Zehra, Mutti, Michele, Restrepo-Córdoba, Marcela, Hartmann, Susana, Kremers, Ana Isabel, Tišáková, Lenka, Schertler, Susanne, Wittmann, Johannes, Kalali, Benham, Monecke, Stefan, Ehricht, Ralf, Resch, Grégory, Corsini, Lorenzo
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 02.04.2021
MDPI
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ISSN1424-8247
1424-8247
DOI10.3390/ph14040325

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Abstract Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε2) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε2-phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε2-phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 1011). In summary, ε2-phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections.
AbstractList Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε2) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε2-phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε2-phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 1011). In summary, ε2-phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections.
Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε2) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε2-phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε2-phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 1011). In summary, ε2-phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections.Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε2) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε2-phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε2-phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 1011). In summary, ε2-phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections.
Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε 2 ) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε 2 -phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε 2 -phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 10 11 ). In summary, ε 2 -phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections.
Author Tišáková, Lenka
Kalali, Benham
Kremers, Ana Isabel
Ehricht, Ralf
Visram, Zehra
Wittmann, Johannes
Corsini, Lorenzo
Resch, Grégory
Hartmann, Susana
Mutti, Michele
Monecke, Stefan
Restrepo-Córdoba, Marcela
Schertler, Susanne
Sáez Moreno, David
AuthorAffiliation 8 Department of Fundamental Microbiology, University Lausanne, CH-1015 Lausanne, Switzerland; gregory.resch@unil.ch
5 Institute of Medical Microbiologye and Hygiene, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Fiedlerstr. 42, D-01307 Dresden, Germany
6 InfectoGnostics Research Campus Jena, 07743 Jena, Germany
1 PhagoMed Biopharma GmbH, Leberstrasse 20, A-1110 Vienna, Austria; david.saez@phagomed.com (D.S.M.); Zehra.visram@phagomed.com (Z.V.); Michele.mutti@phagomed.com (M.M.); Marcela.restrepo@phagomed.com (M.R.-C.); susana.hartmann@phagomed.com (S.H.); kremers.ana@gmail.com (A.I.K.); Lenka.tisakova@phagomed.com (L.T.)
2 Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures, Inhoffenstraße 7B, 38124 Braunschweig, Germany; susanne_schertler@web.de (S.S.); jow12@dsmz.de (J.W.)
3 Bactrace Biotec AG, Neherstr. 1, 81675 Munich, Germany; b.kalali@bactrace.com
4 Leibniz Institute of Photonic Technology (IPHT), 07745 Jena, Germany; stefan.monecke@leibn
AuthorAffiliation_xml – name: 2 Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures, Inhoffenstraße 7B, 38124 Braunschweig, Germany; susanne_schertler@web.de (S.S.); jow12@dsmz.de (J.W.)
– name: 6 InfectoGnostics Research Campus Jena, 07743 Jena, Germany
– name: 1 PhagoMed Biopharma GmbH, Leberstrasse 20, A-1110 Vienna, Austria; david.saez@phagomed.com (D.S.M.); Zehra.visram@phagomed.com (Z.V.); Michele.mutti@phagomed.com (M.M.); Marcela.restrepo@phagomed.com (M.R.-C.); susana.hartmann@phagomed.com (S.H.); kremers.ana@gmail.com (A.I.K.); Lenka.tisakova@phagomed.com (L.T.)
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Snippet Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus...
Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus...
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SubjectTerms antimicrobial resistance
Epidemiology
Genomes
homologous recombination
host range
phage breeding
phage therapy
phage training
Staphylococcus infections
Virulence
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Title ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages
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Volume 14
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