{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T11:50:14Z","timestamp":1768996214783,"version":"3.49.0"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Daptomycin is a lipopeptide antibiotic used clinically for the treatment of methicillin-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Staphylococcus aureus<\/jats:named-content>\n            (MRSA) infections. The emergence of daptomycin-nonsusceptible\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>\n            isolates during therapy is often associated with multiple genetic changes; however, the relative contributions of these changes to resistance and other phenotypic changes usually remain unclear. The present study was undertaken to investigate this issue using a genetically characterized series of four isogenic clinical MRSA strains derived from a patient with bacteremia before and during daptomycin treatment. The first strain obtained after daptomycin therapy carried a single-nucleotide polymorphism (SNP) in\n            <jats:italic>rpoB<\/jats:italic>\n            (RpoB A\n            <jats:sub>477<\/jats:sub>\n            D) that decreased susceptibility not only to daptomycin but also to vancomycin, \u03b2-lactams, and rifampin. Furthermore, the\n            <jats:italic>rpoB<\/jats:italic>\n            mutant exhibited pleiotropic phenotypes, including increased cell wall thickness, reduced expression of virulence traits, induced expression of the stress-associated transcriptional regulator Spx, and slow growth. A subsequently acquired loss-of-function mutation in\n            <jats:italic>clpX<\/jats:italic>\n            partly alleviated the growth defect conferred by the\n            <jats:italic>rpoB<\/jats:italic>\n            mutation without changing antibiotic susceptibility. The final isolate acquired three additional mutations, including an SNP in\n            <jats:italic>mprF<\/jats:italic>\n            (MprF S\n            <jats:sub>295<\/jats:sub>\n            L) known to confer daptomycin nonsusceptibility, and accordingly, this isolate was the only daptomycin-nonsusceptible strain of this series. Interestingly, in this isolate, the cell wall had regained the same thickness as that of the parental strain, while the level of transcription of the\n            <jats:italic>vraSR<\/jats:italic>\n            (cell wall stress regulator) was increased. In conclusion, this study illustrates how serial genetic changes selected\n            <jats:italic>in vivo<\/jats:italic>\n            contribute to daptomycin nonsusceptibility, growth fitness, and virulence traits.\n          <\/jats:p>","DOI":"10.1128\/aac.01303-15","type":"journal-article","created":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T01:59:49Z","timestamp":1441072789000},"page":"6983-6991","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":79,"title":["Stepwise Decrease in Daptomycin Susceptibility in Clinical Staphylococcus aureus Isolates Associated with an Initial Mutation in\n            <i>rpoB<\/i>\n            and a Compensatory Inactivation of the\n            <i>clpX<\/i>\n            Gene"],"prefix":"10.1128","volume":"59","author":[{"given":"Kristoffer T.","family":"B\u00e6k","sequence":"first","affiliation":[{"name":"Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise","family":"Th\u00f8gersen","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9 G.","family":"Mogenssen","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maiken","family":"Mellergaard","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Line E.","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Petersen","sequence":"additional","affiliation":[{"name":"Statens Serum Institute, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00f8ren","family":"Skov","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Monash University, Melbourne, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton 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