Analysis of selection methods to develop novel phage therapy cocktails against antimicrobial resistant clinical isolates of bacteria

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dc.contributor.authorHaines, Melissa E. K.en
dc.contributor.authorHodges, Francesca E.en
dc.contributor.authorNale, Janet Y.en
dc.contributor.authorMahony, Jenniferen
dc.contributor.authorvan Sinderen, Douween
dc.contributor.authorKaczorowska, Joannaen
dc.contributor.authorAlrashid, Bandaren
dc.contributor.authorAkter, Mahmudaen
dc.contributor.authorBrown, Nathanen
dc.contributor.authorSauvageau, Dominicen
dc.contributor.authorSicheritz-Pontén, Thomasen
dc.contributor.authorThanki, Anisha M.en
dc.contributor.authorMillard, Andrew D.en
dc.contributor.authorGalyov, Edouard E.en
dc.contributor.authorClokie, Martha R. J.en
dc.contributor.funderNational Institute for Health and Care Researchen
dc.contributor.funderMinistry of Education in Saudi Arabiaen
dc.date.accessioned2024-01-11T15:21:13Z
dc.date.available2024-01-11T15:21:13Z
dc.date.issued2021en
dc.description.abstractAntimicrobial resistance (AMR) is a major problem globally. The main bacterial organisms associated with urinary tract infection (UTI) associated sepsis are E. coli and Klebsiella along with Enterobacter species. These all have AMR strains known as ESBL (Extended Spectrum Beta-Lactamase), which are featured on the WHO priority pathogens list as “critical” for research. Bacteriophages (phages), as viruses that can infect and kill bacteria, could provide an effective tool to tackle these AMR strains. There is currently no “gold standard” for developing a phage cocktail. Here we describe a novel approach to develop an effective phage cocktail against a set of ESBL-producing E. coli and Klebsiella largely isolated from patients in United Kingdom hospitals. By comparing different measures of phage efficacy, we show which are the most robust, and suggest an efficient screening cascade that could be used to develop phage cocktails to target other AMR bacterial species. A target panel of 38 ESBL-producing clinical strains isolated from urine samples was collated and used to test phage efficacy. After an initial screening of 68 phages, six were identified and tested against these 38 strains to determine their clinical coverage and killing efficiency. To achieve this, we assessed four different methods to assess phage virulence across these bacterial isolates. These were the Direct Spot Test (DST), the Efficiency of Plating (EOP) assay, the planktonic killing assay (PKA) and the biofilm assay. The final ESBL cocktail of six phages could effectively kill 23/38 strains (61%), for Klebsiella 13/19 (68%) and for E. coli 10/19 (53%) based on the PKA data. The ESBL E. coli collection had six isolates from the prevalent UTI-associated ST131 sequence type, five of which were targeted effectively by the final cocktail. Of the four methods used to assess phage virulence, the data suggests that PKAs are as effective as the much more time-consuming EOPs and data for the two assays correlates well. This suggests that planktonic killing is a good proxy to determine which phages should be used in a cocktail. This assay when combined with the virulence index also allows “phage synergy” to inform cocktail design.en
dc.description.sponsorshipNational Institute for Health Research (NIHR Academic Clinical Fellowship); Ministry of Education in Saudi Arabia (Grant KSU/1480/E)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid613529en
dc.identifier.citationHaines, M.E.K., Hodges, F.E., Nale, J.Y., Mahony, J., Van Sinderen, D., Kaczorowska, J., Alrashid, B., Akter, M., Brown, N., Sauvageau, D., Sicheritz-Pontén, T., Thanki, A.M., Millard, A.D., Galyov, E.E. and Clokie, M.R.J. (2021) ‘Analysis of selection methods to develop novel phage therapy cocktails against antimicrobial resistant clinical isolates of bacteria’, Frontiers in Microbiology, 12, 613529 (15pp). doi: 10.3389/fmicb.2021.613529en
dc.identifier.doi10.3389/fmicb.2021.613529en
dc.identifier.endpage15en
dc.identifier.issn1664-302Xen
dc.identifier.journaltitleFrontiers in Microbiologyen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/15358
dc.identifier.volume12en
dc.language.isoenen
dc.publisherFrontiers Media S.A.en
dc.relation.ispartofFrontiers in Microbiologyen
dc.rights© 2021 Haines, Hodges, Nale, Mahony, van Sinderen, Kaczorowska, Alrashid, Akter, Brown, Sauvageau, Sicheritz-Pontén, Thanki, Millard, Galyov and Clokie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectAntimicrobial resistanceen
dc.subjectAntibiotic resistanceen
dc.subjectUrinary tract infectionen
dc.subjectBacteriophageen
dc.subjectPhage therapyen
dc.subjectESBLen
dc.subjectE. colien
dc.subjectKlebsiellaen
dc.titleAnalysis of selection methods to develop novel phage therapy cocktails against antimicrobial resistant clinical isolates of bacteriaen
dc.typeArticle (peer-reviewed)en
dc.typejournal-articleen
oaire.citation.volume12en
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