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Open AccessArticle

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

1
PhagoMed Biopharma GmbH, Leberstrasse 20, A-1110 Vienna, Austria
2
Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures, Inhoffenstraße 7B, 38124 Braunschweig, Germany
3
Bactrace Biotec AG, Neherstr. 1, 81675 Munich, Germany
4
Leibniz Institute of Photonic Technology (IPHT), 07745 Jena, Germany
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
7
Institute of Physical Chemistry, Friedrich-Schiller University, 07743 Jena, Germany
8
Department of Fundamental Microbiology, University Lausanne, CH-1015 Lausanne, Switzerland
*
Author to whom correspondence should be addressed.
Academic Editors: Paul Hyman, Christine Schneider and Bryan Gibb
Pharmaceuticals 2021, 14(4), 325; https://doi.org/10.3390/ph14040325
Received: 29 January 2021 / Revised: 22 February 2021 / Accepted: 23 February 2021 / Published: 2 April 2021
(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)
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. View Full-Text
Keywords: phage therapy; phage breeding; phage training; homologous recombination; host range; antimicrobial resistance; phage cocktail; S. aureus; MRSA; MSSA phage therapy; phage breeding; phage training; homologous recombination; host range; antimicrobial resistance; phage cocktail; S. aureus; MRSA; MSSA
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MDPI and ACS Style

Sáez Moreno, D.; Visram, Z.; Mutti, M.; Restrepo-Córdoba, M.; Hartmann, S.; Kremers, A.I.; Tišáková, L.; Schertler, S.; Wittmann, J.; Kalali, B.; Monecke, S.; Ehricht, R.; Resch, G.; Corsini, L. ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages. Pharmaceuticals 2021, 14, 325. https://doi.org/10.3390/ph14040325

AMA Style

Sáez Moreno D, Visram Z, Mutti M, Restrepo-Córdoba M, Hartmann S, Kremers AI, Tišáková L, Schertler S, Wittmann J, Kalali B, Monecke S, Ehricht R, Resch G, Corsini L. ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages. Pharmaceuticals. 2021; 14(4):325. https://doi.org/10.3390/ph14040325

Chicago/Turabian Style

Sáez Moreno, David; Visram, Zehra; Mutti, Michele; Restrepo-Córdoba, Marcela; Hartmann, Susana; Kremers, Ana I.; Tišáková, Lenka; Schertler, Susanne; Wittmann, Johannes; Kalali, Benham; Monecke, Stefan; Ehricht, Ralf; Resch, Grégory; Corsini, Lorenzo. 2021. "ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages" Pharmaceuticals 14, no. 4: 325. https://doi.org/10.3390/ph14040325

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