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Daptomycin, a last-line treatment for VRE, often loses efficacy due to the emergence of resistance. In this study, we revealed the critical role of the\n                      <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                      gene as a key determinant of daptomycin susceptibility and resistance in\n                      <jats:italic toggle=\"yes\">E. faecium<\/jats:italic>\n                      . We showed that in the absence of a functional\n                      <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                      , daptomycin-resistant mutants did not emerge\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , and derivatives of clinical daptomycin-resistant strains engineered to lack functional\n                      <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                      were rendered even more sensitive to daptomycin than wild-type daptomycin-susceptible strains. These findings indicated that functional\n                      <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                      is critical for key known mechanisms of daptomycin resistance, and mutations in\n                      <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                      have phenotypic dominance to those that otherwise confer resistance. Therefore, inhibiting the activity of the\n                      <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                      gene product is predicted to prevent or reverse resistance, offering a promising new strategy for extending the efficacy of daptomycin for treating enterococcal infections.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Daptomycin is one of the few remaining effective antibiotics for treating vancomycin-resistant enterococcal infections but is limited by the emergence of resistance during protracted therapy. Here, we show that without a functional\n                        <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                        gene, daptomycin-resistant mutants do not arise under conditions where wild-type strains readily generate daptomycin-resistant mutants. Furthermore, we show that loss of function mutation of the\n                        <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                        gene in daptomycin-resistant clinical isolates renders them more susceptible to daptomycin than wild-type\n                        <jats:italic toggle=\"yes\">Enterococcus faecium<\/jats:italic>\n                        . This indicates that an effective small molecule inhibitor of LafB activity or\n                        <jats:italic toggle=\"yes\">lafB<\/jats:italic>\n                        gene expression would be a useful adjunctive for extending and restoring the therapeutic utility of daptomycin.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00715-25","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:54:35Z","timestamp":1764334475000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Loss of LafB activity reverses daptomycin resistance in\n                    <i>E. faecium<\/i>"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6389-6041","authenticated-orcid":true,"given":"Suelen","family":"Scarpa de Mello","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04g3dn724","id-type":"ROR","asserted-by":"publisher"}],"name":"Massachusetts Eye and Ear Infirmary","place":["Boston, USA"]},{"name":"Harvard Medical School, Microbiology Department, Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Schultz","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Microbiology Department, Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byoungsook","family":"Goh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Grote","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ets8c94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, Northwestern University Feinberg School of Medicine","place":["Chicago, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terrance","family":"Shea","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05a0ya142","id-type":"ROR","asserted-by":"publisher"}],"name":"Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Muscato","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gh96r95","id-type":"ROR","asserted-by":"publisher"}],"name":"Biology Department, Bowdoin College","place":["Brunswick, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungwhan F.","family":"Oh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital","place":["Boston, USA"]},{"name":"Graduate Program in Immunology, Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3800-0714","authenticated-orcid":false,"given":"Abigail L.","family":"Manson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05a0ya142","id-type":"ROR","asserted-by":"publisher"}],"name":"Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7857-9145","authenticated-orcid":true,"given":"Ashlee M.","family":"Earl","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05a0ya142","id-type":"ROR","asserted-by":"publisher"}],"name":"Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0545-914X","authenticated-orcid":true,"given":"Suzanne","family":"Walker","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Microbiology Department, Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4489-1215","authenticated-orcid":true,"given":"Ilana L. 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