{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:50:51Z","timestamp":1790686251882,"version":"4.1.0"},"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T00:00:00Z","timestamp":1724889600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R21 AI144769-01A1"],"award-info":[{"award-number":["1R21 AI144769-01A1"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Vancomycin has proven remarkably durable to resistance evolution by <jats:italic>Staphylococcus aureus<\/jats:italic> despite widespread treatment with vancomycin in the clinic. Only 16 cases of vancomycin-resistant <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic> (VRSA) have been documented in the United States. It is thought that the failure of VRSA to spread is partly due to the fitness cost imposed by the <jats:italic>vanA<\/jats:italic> operon, which is the only known means of high-level resistance. Here, we show that the fitness cost of <jats:italic>vanA<\/jats:italic>-mediated resistance can be overcome through laboratory evolution of VRSA in the presence of vancomycin. Adaptation to vancomycin imposed a tradeoff such that fitness in the presence of vancomycin increased, while fitness in its absence decreased in evolved lineages. Comparing the genomes of vancomycin-exposed and vancomycin-unexposed lineages pinpointed the D-alanine:D-alanine ligase gene (<jats:italic>ddl<\/jats:italic>) as the target of loss-of-function mutations, which were associated with the observed fitness tradeoff. Vancomycin-exposed lineages exhibited vancomycin dependence and abnormal colony morphology in the absence of drug, which were associated with mutations in <jats:italic>ddl<\/jats:italic>. However, further evolution of vancomycin-exposed lineages in the absence of vancomycin enabled some evolved lineages to escape this fitness tradeoff. Many vancomycin-exposed lineages maintained resistance in the absence of vancomycin, unlike their ancestral VRSA strains. These results indicate that VRSA might be able to compensate for the fitness deficit associated with <jats:italic>vanA<\/jats:italic>-mediated resistance, which may pose a threat to the prolonged durability of vancomycin in the clinic. Our results also suggest vancomycin treatment should be immediately discontinued in patients after VRSA is identified to mitigate potential adaptations.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012422","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T17:32:07Z","timestamp":1724952727000},"page":"e1012422","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Vancomycin-resistant Staphylococcus aureus (VRSA) can overcome the cost of antibiotic resistance and may threaten vancomycin\u2019s clinical durability"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6878-6411","authenticated-orcid":true,"given":"Samuel E.","family":"Blechman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1457-4019","authenticated-orcid":true,"given":"Erik S.","family":"Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"ppat.1012422.ref001","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1086\/516375","article-title":"Why Have Group A Streptococci Remained Susceptible to Penicillin? 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