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Acton, Luke, Pye, Hannah V., Thilliez, Gaëtan, Kolenda, Rafał, Matthews, Michaela, Turner, A. Keith, Yasir, Muhammad, Holden, Emma, Al-Khanaq, Haider, Webber, Mark, Adriaenssens, Evelien M. and Kingsley, Robert A. 
ORCID: https://orcid.org/0000-0002-0194-6485
(2024)
Collateral sensitivity increases the efficacy of a rationally designed bacteriophage combination to control Salmonella enterica.
Journal of Virology, 98 (3).
ISSN 0022-538X
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Abstract
The ability of virulent bacteriophages to lyse bacteria influences bacterial evolution, fitness, and population structure. Knowledge of both host susceptibility and resistance factors is crucial for the successful application of bacteriophages as biological control agents in clinical therapy, food processing, and agriculture. In this study, we isolated 12 bacteriophages termed SPLA phage which infect the foodborne pathogen Salmonella enterica. To determine phage host range, a diverse collection of Enterobacteriaceae and Salmonella enterica was used and genes involved in infection by six SPLA phages were identified using Salmonella Typhimurium strain ST4/74. Candidate host receptors included lipopolysaccharide (LPS), cellulose, and BtuB. Lipopolysaccharide was identified as a susceptibility factor for phage SPLA1a and mutations in LPS biosynthesis genes spontaneously emerged during culture with S. Typhimurium. Conversely, LPS was a resistance factor for phage SPLA5b which suggested that emergence of LPS mutations in culture with SPLA1a represented collateral sensitivity to SPLA5b. We show that bacteria-phage co-culture with SPLA1a and SPLA5b was more successful in limiting the emergence of phage resistance compared to single phage co-culture. Identification of host susceptibility and resistance genes and understanding infection dynamics are critical steps in the rationale design of phage cocktails against specific bacterial pathogens. IMPORTANCE As antibiotic resistance continues to emerge in bacterial pathogens, bacterial viruses (phage) represent a potential alternative or adjunct to antibiotics. One challenge for their implementation is the predisposition of bacteria to rapidly acquire resistance to phages. We describe a functional genomics approach to identify mechanisms of susceptibility and resistance for newly isolated phages that infect and lyse Salmonella enterica and use this information to identify phage combinations that exploit collateral sensitivity, thus increasing efficacy. Collateral sensitivity is a phenomenon where resistance to one class of antibiotics increases sensitivity to a second class of antibiotics. We report a functional genomics approach to rationally design a phage combination with a collateral sensitivity dynamic which resulted in increased efficacy. Considering such evolutionary tradeoffs has the potential to manipulate the outcome of phage therapy in favor of resolving infection without selecting for escape mutants and is applicable to other virus-host interactions.
| Item Type: | Article |
|---|---|
| Additional Information: | Data Availability Statement: The genome sequence of SPLA phages are publicly available within NCBI with individual accessions listed in Table 1. Sequence reads of bacteria are deposited within the Sequence Read Archive (SRA) with accessions listed in Table S1. TraDIS sequencing reads are deposited within SRA and available under the project PRJNA1004457. Bacteriophage sequencing reads are available under the project code PRJNA1031836. Funding Information: The author(s) gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); this research was funded by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent projects BBS/E/F/000PR10348 and BBS/E/F/000PR10349 and the BBSRC Institute Strategic Programme Microbes and Food Safety BB/X011011/1 and its constituent projects, BBS/E/F/000PR13635 and BBS/E/F/000PR13636. L.A. was supported by the UKRI Biotechnology and Biological Sciences Research Council Norwich Research Park Biosciences Doctoral Training Partnership as a CASE Award, BB/ M011216/1. |
| Uncontrolled Keywords: | antimicrobial,btub,collateral sensitivity,lps,phage,tradis,microbiology,immunology,insect science,virology ,/dk/atira/pure/subjectarea/asjc/2400/2404 |
| Faculty \ School: | Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 23 Oct 2024 11:30 |
| Last Modified: | 25 Oct 2024 15:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/97146 |
| DOI: | 10.1128/jvi.01476-23 |
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