{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:58:07Z","timestamp":1793235487169,"version":"4.5.0"},"reference-count":70,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["24POST1183502"],"award-info":[{"award-number":["24POST1183502"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01AI141479"],"award-info":[{"award-number":["R01AI141479"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Bacteriol"],"published-print":{"date-parts":[[2025,11,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Enterococcus faecium<\/jats:italic>\n                      is a gram-positive bacterium that is resident to the intestines of animals including humans.\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      is also an opportunistic pathogen that causes multidrug-resistant (MDR) infections. Bacteriophages (phages) have been proposed as therapeutics for the treatment of MDR infections; however, an obstacle for phage therapy is the emergence of phage resistance. Despite this, the development of phage resistance can impact bacterial fitness. Thus, understanding the molecular basis of fitness costs associated with phage resistance can likely be leveraged as an antimicrobial strategy. We discovered that phage-resistant\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      harbor mutations in the cell wall hydrolase gene\n                      <jats:italic toggle=\"yes\">sagA<\/jats:italic>\n                      . SagA cleaves crosslinked peptidoglycan (PG) involved in PG remodeling. We show that mutations in\n                      <jats:italic toggle=\"yes\">sagA<\/jats:italic>\n                      compromised\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      PG hydrolysis. One\n                      <jats:italic toggle=\"yes\">sagA<\/jats:italic>\n                      mutant, with a defect in cell envelope integrity, increased cellular permeability, and aberrant distribution of penicillin-binding proteins, was also more sensitive to \u03b2-lactam antibiotics. These changes correspond to a growth defect where cells have abnormal division septa, membrane blebbing, and aberrant cell shape. The dysregulation of the cell envelope caused by the\n                      <jats:italic toggle=\"yes\">sagA<\/jats:italic>\n                      mutation alters the binding of phages to the\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      cell surface, where phage infection of\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      requires phages to localize to sites of peptidoglycan remodeling. Our findings show that by altering the function of a single PG hydrolase,\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      loses intrinsic \u03b2-lactam resistance. This indicates that phage therapy could help revive certain antibiotics when used in combination.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Enterococcus faecium<\/jats:italic>\n                        causes hospital-acquired infections and is frequently resistant to frontline antibiotics, including those that target the cell wall. Bacteriophages represent a promising alternative to combat such infections. However, bacterial adaptation to phage predation often results in resistance. Such resistance is frequently accompanied by fitness trade-offs, most notably altered antibiotic susceptibility. This study provides mechanistic insights into phage resistance-associated antibiotic sensitivity in\n                        <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                        . We show that phage-resistant\n                        <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                        carrying a mutation in the peptidoglycan hydrolase SagA has compromised cell envelope integrity, mislocalized penicillin-binding proteins, and become sensitized to \u03b2-lactam antibiotics. These findings highlight the potential of reviving antibiotics when used in combination with phages in the clinical setting.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00302-25","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T13:22:23Z","timestamp":1760016143000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["<i>Enterococcus faecium sagA<\/i>\n                    mutants have cell envelope defects influencing antibiotic resistance and bacteriophage susceptibility"],"prefix":"10.1128","volume":"207","author":[{"given":"Garima","family":"Arya","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado \u2013 Anschutz Medical Campus, School of Medicine","place":["Aurora, 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