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While phage therapy is proposed as a solution to the antibiotic resistance crisis, the bacterial resistance emerging during phage therapy remains poorly characterized. In this study, we examined a large population of phage-resistant extra-intestinal pathogenic\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      536 clones that emerged from both\n                      <jats:italic>in vitro<\/jats:italic>\n                      (non-limited liquid medium) and\n                      <jats:italic>in vivo<\/jats:italic>\n                      (murine pneumonia) conditions. Genome sequencing uncovered a convergent mutational pattern in phage resistance mechanisms under both conditions, particularly targeting two cell-wall components, the K15 capsule and the lipopolysaccharide (LPS). This suggests that their identification\n                      <jats:italic>in vivo<\/jats:italic>\n                      could be predicted from\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays. Phage-resistant clones exhibited a wide range of fitness according to\n                      <jats:italic>in vitro<\/jats:italic>\n                      tests, growth rate, and resistance to amoeba grazing, which could not distinguish between the K15 capsule and LPS mutants. In contrast, K15 capsule mutants retained virulence comparable to the wild-type strain, whereas LPS mutants showed significant attenuation in the murine pneumonia model. Additionally, we observed that resistance to the therapeutic phage through a nonspecific mechanism, such as capsule overproduction, did not systematically lead to co-resistance to other phages that were initially capable or incapable of infecting the wild-type strain. Our findings highlight the importance of incorporating a diverse range of phages in the design of therapeutic cocktails to target potential future phage-resistant clones effectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      This study isolated more than 50 phage-resistant mutants from both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      conditions, exposing an extra-intestinal pathogenic\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      strain to a single virulent phage. The characterization of these clones revealed several key findings: (1) mutations occurring during phage treatment affect the same pathways as those identified\n                      <jats:italic>in vitro<\/jats:italic>\n                      ; (2) the resistance mechanisms are associated with the modification of two cell-wall components, with one involving receptor deletion (phage-specific mechanism) and the other, less frequent, involving receptor masking (phage-nonspecific mechanism); (3) an\n                      <jats:italic>in vivo<\/jats:italic>\n                      virulence assay demonstrated that the absence of the receptor abolishes virulence while masking the receptor preserves it; and (4) clones with a resistance mechanism nonspecific to a particular phage can remain susceptible to other phages. This supports the idea of incorporating diverse phages into therapeutic cocktails designed to collectively target both wild-type and phage-resistant strains, including those with resistance mechanisms nonspecific to a phage.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01113-24","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T12:41:14Z","timestamp":1725021674000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["Variable fitness effects of bacteriophage resistance mutations in\n                    <i>Escherichia coli:<\/i>\n                    implications for phage therapy"],"prefix":"10.1128","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9586-3014","authenticated-orcid":true,"given":"Baptiste","family":"Gaborieau","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM UMR1137, 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Clermont","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM UMR1137, IAME, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7860-1717","authenticated-orcid":true,"given":"Erick","family":"Denamur","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM UMR1137, IAME, Paris, France"},{"name":"APHP, H\u00f4pital Bichat, Service de G\u00e9n\u00e9tique Mol\u00e9culaire, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1828-2299","authenticated-orcid":false,"given":"Jean-Damien","family":"Ricard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM UMR1137, IAME, Paris, France"},{"name":"APHP, H\u00f4pital Louis Mourier, DMU ESPRIT, Service de M\u00e9decine Intensive 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