{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T02:28:07Z","timestamp":1776738487571,"version":"3.51.2"},"reference-count":57,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2008,11,1]],"date-time":"2008-11-01T00:00:00Z","timestamp":1225497600000},"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":[[2008,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Recent cases of infections caused by community-acquired methicillin-resistant\n            <jats:italic>Staphylococcus aureus<\/jats:italic>\n            (MRSA) (CA-MRSA) strains in healthy individuals have raised concerns worldwide. CA-MRSA strains differ from hospital-acquired MRSAs by virtue of their genomic background and increased virulence in animal models. Here, we show that in two common CA-MRSA isolates, USA300 and MW2 (USA400), a loss of penicillin binding protein 4 (PBP4) is sufficient to cause a 16-fold reduction in oxacillin and nafcillin resistance, thus demonstrating that\n            <jats:italic>mecA<\/jats:italic>\n            , encoding PBP2A, is not the sole determinant of methicillin resistance in CA-MRSA. The loss of PBP4 was also found to severely affect the transcription of PBP2 in cells after challenge with oxacillin, thus leading to a significant decrease in peptidoglycan cross-linking. Autolysis, which is commonly associated with the killing mechanism of penicillin and \u03b2-lactams, does not play a role in the reduced resistance phenotype associated with the loss of PBP4. We also showed that cefoxitin, a semisynthetic \u03b2-lactam that binds irreversibly to PBP4, is synergistic with oxacillin in killing CA-MRSA strains, including clinical CA-MRSA isolates. Thus, PBP4 represents a major target for drug rediscovery against CA-MRSA, and a combination of cefoxitin and synthetic penicillins may be an effective therapy for CA-MRSA infections.\n          <\/jats:p>","DOI":"10.1128\/aac.00049-08","type":"journal-article","created":{"date-parts":[[2008,8,26]],"date-time":"2008-08-26T00:45:17Z","timestamp":1219711517000},"page":"3955-3966","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":153,"title":["<i>Staphylococcus aureus<\/i>\n            PBP4 Is Essential for \u03b2-Lactam Resistance in Community-Acquired Methicillin-Resistant Strains"],"prefix":"10.1128","volume":"52","author":[{"given":"Guido","family":"Memmi","sequence":"first","affiliation":[{"name":"Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire"}]},{"given":"Sergio R.","family":"Filipe","sequence":"additional","affiliation":[{"name":"Bacterial Cell Surfaces and Pathogenesis Laboratory"}]},{"given":"Mariana G.","family":"Pinho","sequence":"additional","affiliation":[{"name":"Bacterial Cell Biology Laboratory, Instituto de Tecnologia Qui\u0301mica e Biolo\u0301gica, Oeiras, Portugal"}]},{"given":"Zhibiao","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire"}]},{"given":"Ambrose","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/520289"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.70.11.6887-6891.2004"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08713-5"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1106.040885"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-0711-5-29"},{"key":"e_1_3_2_7_2","unstructured":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard 7th ed. 2006"},{"key":"e_1_3_2_8_2","first-page":"1271","volume":"77","year":"2006","unstructured":"Cloran, F. 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