{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:50:27Z","timestamp":1792705827788,"version":"4.5.0"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2008,6,1]],"date-time":"2008-06-01T00:00:00Z","timestamp":1212278400000},"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":[[2008,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Methicillin-resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (MRSA) is resistant to \u03b2-lactam antibiotics because it expresses penicillin-binding protein 2a (PBP2a), a low-affinity penicillin-binding protein. An investigational broad-spectrum cephalosporin, ceftobiprole (BPR), binds PBP2a with high affinity and is active against MRSA. We hypothesized that BPR resistance could be mediated by mutations in\n                    <jats:italic>mecA<\/jats:italic>\n                    , the gene encoding PBP2a. We selected BPR-resistant mutants by passage in high-volume broth cultures containing subinhibitory concentrations of BPR. We used strain COLnex (which lacks chromosomal\n                    <jats:italic>mecA<\/jats:italic>\n                    ) transformed with pAW8 (a plasmid vector only), pYK20 (a plasmid carrying wild-type\n                    <jats:italic>mecA<\/jats:italic>\n                    ), or pYK21 (a plasmid carrying a mutant\n                    <jats:italic>mecA<\/jats:italic>\n                    gene corresponding to five PBP2a mutations). All strains became resistant to BPR by day 9 of passaging, but MICs continued to increase until day 21. MICs increased 256-fold (from 1 to 256 \u03bcg\/ml) for pAW8, 32-fold (from 4 to 128 \u03bcg\/ml) for pYK20, and 8-fold (from 16 to 128 \u03bcg\/ml) for pYK21. Strains carrying wild-type or mutant\n                    <jats:italic>mecA<\/jats:italic>\n                    developed six (pYK20 transformants) or four (pYK21 transformants) new mutations in\n                    <jats:italic>mecA<\/jats:italic>\n                    . The transformation of COLnex with a\n                    <jats:italic>mecA<\/jats:italic>\n                    mutant plasmid conferred BPR resistance, and the loss of\n                    <jats:italic>mecA<\/jats:italic>\n                    converted resistant strains into susceptible ones. Modeling studies predicted that several of the\n                    <jats:italic>mecA<\/jats:italic>\n                    mutations altered BPR binding; other mutations may have mediated resistance by influencing interactions with other proteins. Multiple\n                    <jats:italic>mecA<\/jats:italic>\n                    mutations were associated with BPR resistance in MRSA. BPR resistance also developed in the strain lacking\n                    <jats:italic>mecA<\/jats:italic>\n                    , suggesting a role for chromosomal genes.\n                  <\/jats:p>","DOI":"10.1128\/aac.01403-07","type":"journal-article","created":{"date-parts":[[2008,3,31]],"date-time":"2008-03-31T20:46:09Z","timestamp":1206996369000},"page":"2089-2096","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":73,"title":["In Vitro Selection and Characterization of Ceftobiprole-Resistant Methicillin-Resistant\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","volume":"52","author":[{"given":"Ritu","family":"Banerjee","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gretes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology and the Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Basuino","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Strynadka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology and the Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry F.","family":"Chambers","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"3","volume":"12","year":"2006","unstructured":"Appelbaum, P. C. 2006. MRSA\u2014the tip of the iceberg. Clin. Microbiol. Infect.12(Suppl. 2):3-10.","journal-title":"Clin. Microbiol. Infect."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.10.4210-4219.2005"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200708001"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00124a002"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00029-07"},{"key":"e_1_3_2_7_2","unstructured":"The PyMOL molecular graphics system. 2002"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.11.2590"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/elps.1150181505"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2004.00774.x"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.2.453-459.2004"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.185.18.5465-5472.2003"},{"key":"e_1_3_2_13_2","first-page":"329","volume":"4","year":"2003","unstructured":"Katayama, Y., H.-Z. Zhong, and H. F. Chambers. 2003. Effect of disruption of Staphylococcus aureus PBP4 gene on resistance to \u03b2-lactam antibiotics. Microb. Drug Resist.4:329-336.","journal-title":"Microb. Drug Resist."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/42.2.227"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.12.4665-4672.2004"},{"key":"e_1_3_2_16_2","unstructured":"APBS plug-in for PyMOL. 2006"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.187.5.1815-1824.2005"},{"key":"e_1_3_2_18_2","first-page":"870","volume":"9","year":"2002","unstructured":"Lim, D., and N. C. Strynadka. 2002. Structural basis for the \u03b2-lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat. Struct. Biol9:870-876.","journal-title":"Nat. Struct. 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