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The two most prominent species associated with humans, Enterococcus faecalis and Enterococcus faecium, have also emerged as prominent opportunistic pathogens causing a range of infections in hospitalized patients, including urinary tract infections, bloodstream infections, and endocarditis. The rise of antibiotic resistance in enterococci undermines the efficacy of the treatment of infections, thus posing a significant public health risk. Enterococci readily acquire resistance to antibiotics through chromosomal mutations and the horizontal gene transfer of antibiotic resistance genes. This review offers a comprehensive examination of the mechanisms of antibiotic resistance among enterococci, with an emphasis on resistance to last-line antibiotics, including to glycopeptide antibiotics like vancomycin and teicoplanin, oxazolidinones (primarily linezolid), and daptomycin. Furthermore, we evaluate relevant candidates in the current development pipeline for antibiotics and discuss alternative strategies (phage therapy and immunotherapeutics) for the treatment and prevention of infections with multidrug-resistant enterococci. As enterococci rapidly adapt to novel conditions, including by developing resistance to new drugs and therapies, sustained research efforts are required to ensure the continuous development of treatment options for these important opportunistic pathogens.<\/jats:p>","DOI":"10.1093\/femsre\/fuaf057","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T13:02:38Z","timestamp":1762606958000},"source":"Crossref","is-referenced-by-count":32,"title":["Resistance to last-resort antibiotics in enterococci"],"prefix":"10.1093","volume":"49","author":[{"given":"Zhaoxiang","family":"Lu","sequence":"first","affiliation":[{"name":"Infection and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham Institute of Microbiology and Infection and Department of Microbes, , Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross S","family":"Mclnnes","sequence":"additional","affiliation":[{"name":"Infection and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham Institute of Microbiology and Infection and Department of Microbes, , Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freya","family":"Allen","sequence":"additional","affiliation":[{"name":"Infection and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham Institute of Microbiology and Infection and Department of Microbes, , Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita","family":"Gadar","sequence":"additional","affiliation":[{"name":"Infection and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham Institute of Microbiology and Infection and Department of Microbes, , Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5832-0988","authenticated-orcid":false,"given":"Willem","family":"van\u00a0Schaik","sequence":"additional","affiliation":[{"name":"Infection and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham Institute of Microbiology and Infection and Department of Microbes, , Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"key":"2025112403213613100_bib1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1093\/jac\/dkac434","article-title":"Emerging resistance in Staphylococcus epidermidis during dalbavancin exposure: a case report and in vitro analysis of isolates from prosthetic joint 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