{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:54:19Z","timestamp":1785405259746,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,11]]},"group-title":"Microbiology","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21AT012958"],"award-info":[{"award-number":["R21AT012958"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["5P30CA045508"],"award-info":[{"award-number":["5P30CA045508"]}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"crossref","award":["FT170100156"],"award-info":[{"award-number":["FT170100156"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03kz2rg33","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Vancomycin-resistant\n                  <jats:italic>Enterococcus faecium<\/jats:italic>\n                  (VREfm) is a leading cause of healthcare-associated infections globally and demands new approaches for treatment. Here we show that genetic and pharmacological inactivation of a highly conserved NlpC\/P60 peptidoglycan hydrolase, secreted antigen A (SagA), enhanced vancomycin susceptibility of VREfm\n                  <jats:italic>ex vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Notably, genetic deletion of\n                  <jats:italic>sagA<\/jats:italic>\n                  impaired VREfm peptidoglycan remodeling, growth and increased the activity of vancomycin. We then identified first-in-class covalent NlpC\/P60 peptidoglycan hydrolase inhibitors and demonstrated that pharmacological inactivation of SagA activity also impaired peptidoglycan remodeling and increased the efficacy of vancomycin across genetically distinct VREfm clinical isolates. Our study reveals peptidoglycan hydrolases are druggable targets whose inactivation improves the efficacy of vancomycin against VREfm.\n                <\/jats:p>","DOI":"10.1101\/2025.09.11.675460","type":"posted-content","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T05:51:49Z","timestamp":1757656309000},"source":"Crossref","is-referenced-by-count":1,"title":["Genetic and pharmacological inactivation of peptidoglycan remodeling increases antibiotic susceptibility of vancomycin-resistant\n                  <i>Enterococcus faecium<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4877-5679","authenticated-orcid":false,"given":"Kyong T.","family":"Fam","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, Scripps Research; La Jolla, California 92037, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4890-8531","authenticated-orcid":false,"given":"Pavan Kumar","family":"Chodisetti","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Scripps Research; 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