{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:58:15Z","timestamp":1791979095863,"version":"4.4.0"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:00:00Z","timestamp":1709683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:00:00Z","timestamp":1709683200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["K24AI121296, R01AI134637, R01AI148342, P01AI152999"],"award-info":[{"award-number":["K24AI121296, R01AI134637, R01AI148342, P01AI152999"]}]},{"name":"HHS | National Institutes of Health","award":["R01 AI080714"],"award-info":[{"award-number":["R01 AI080714"]}]},{"name":"HHS | National Institutes of Health","award":["T32AI141349, L30AI154520"],"award-info":[{"award-number":["T32AI141349, L30AI154520"]}]},{"name":"Houston Methodist Clinical Scholars Award"},{"name":"HHS | National Institutes of Health","award":["T32AI055449"],"award-info":[{"award-number":["T32AI055449"]}]},{"name":"HHS | National Institutes of Health","award":["K01AI148593, P01AI152999"],"award-info":[{"award-number":["K01AI148593, P01AI152999"]}]},{"name":"HHS | National Institutes of Health","award":["T32 AI141349"],"award-info":[{"award-number":["T32 AI141349"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,3,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Daptomycin (DAP) is often used as a first-line therapy to treat vancomycin-resistant\n                      <jats:italic>Enterococcus faecium<\/jats:italic>\n                      infections, but emergence of DAP non-susceptibility threatens the effectiveness of this antibiotic. Moreover, current methods to determine DAP minimum inhibitory concentrations (MICs) have poor reproducibility and accuracy. In enterococci, DAP resistance is mediated by the LiaFSR cell membrane stress response system, and deletion of\n                      <jats:italic>liaR<\/jats:italic>\n                      encoding the response regulator results in hypersusceptibility to DAP and antimicrobial peptides. The main genes regulated by LiaR are a cluster of three genes, designated\n                      <jats:italic>liaXYZ<\/jats:italic>\n                      . In\n                      <jats:italic>Enterococcus faecalis<\/jats:italic>\n                      , LiaX is surface-exposed with a C-terminus that functions as a negative regulator of cell membrane remodeling and an N-terminal domain that is released to the extracellular medium where it binds DAP. Thus, in\n                      <jats:italic>E. faecalis<\/jats:italic>\n                      , LiaX functions as a sentinel molecule recognizing DAP and controlling the cell membrane response, but less is known about LiaX in\n                      <jats:italic>E. faecium<\/jats:italic>\n                      . Here, we found that\n                      <jats:italic>liaX<\/jats:italic>\n                      is essential in\n                      <jats:italic>E. faecium<\/jats:italic>\n                      with an activated LiaFSR system. Unlike\n                      <jats:italic>E. faecalis<\/jats:italic>\n                      ,\n                      <jats:italic>E. faecium<\/jats:italic>\n                      LiaX is not detected in the extracellular milieu and does not appear to alter phospholipid architecture. We further postulated that LiaX could be used as a surrogate marker for cell envelope activation and non-susceptibility to DAP. For this purpose, we developed and optimized a LiaX enzyme-linked immunosorbent assay (ELISA). We then assessed 86 clinical\n                      <jats:italic>E. faecium<\/jats:italic>\n                      bloodstream isolates for DAP MICs and used whole genome sequencing to assess for substitutions in LiaX. All DAP-resistant clinical strains of\n                      <jats:italic>E. faecium<\/jats:italic>\n                      exhibited elevated LiaX levels. Strikingly, 73% of DAP-susceptible isolates by standard MIC determination also had elevated LiaX ELISAs compared to a well-characterized DAP-susceptible strain. Phylogenetic analyses of predicted amino acid substitutions showed 12 different variants of LiaX without a specific association with DAP MIC or LiaX ELISA values. Our findings also suggest that many\n                      <jats:italic>E. faecium<\/jats:italic>\n                      isolates that test DAP susceptible by standard MIC determination are likely to have an activated cell stress response that may predispose to DAP failure. As LiaX appears to be essential for the cell envelope response to DAP, its detection could prove useful to improve the accuracy of susceptibility testing by anticipating therapeutic failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01069-23","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T09:01:38Z","timestamp":1706605298000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["LiaX is a surrogate marker for cell envelope stress and daptomycin non-susceptibility in\n                    <i>Enterococcus faecium<\/i>"],"prefix":"10.1128","volume":"68","author":[{"given":"Dierdre B.","family":"Axell-House","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA"},{"name":"Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA"},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby R.","family":"Simar","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases, University of Texas Health Science Center, School of Public Health, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Panesso","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA"},{"name":"Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA"},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, USA"},{"name":"Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogot\u00e1, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Rincon","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogot\u00e1, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-2973","authenticated-orcid":true,"given":"William R.","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA"},{"name":"Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA"},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-0712","authenticated-orcid":true,"given":"Ayesha","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orville A.","family":"Pemberton","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Rice University, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizbet","family":"Valdez","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA"},{"name":"Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary N.","family":"Jones","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA"},{"name":"Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Atterstrom","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA"},{"name":"Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1722-0734","authenticated-orcid":true,"given":"Jinnethe","family":"Reyes","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogot\u00e1, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranoti V.","family":"Sahasrabhojane","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geehan","family":"Suleyman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, Henry Ford Hospital, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Zervos","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, Henry Ford Hospital, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9721-263X","authenticated-orcid":true,"given":"Samuel 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