{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:40:21Z","timestamp":1791344421588,"version":"4.3.1"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2014,10,1]],"date-time":"2014-10-01T00:00:00Z","timestamp":1412121600000},"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":[[2014,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Methicillin-resistant<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Staphylococcus aureus<\/jats:named-content>(MRSA) is an important infectious human pathogen responsible for diseases ranging from skin and soft tissue infections to life-threatening endocarditis. \u03b2-Lactam resistance in MRSA involves acquisition of penicillin-binding protein 2a (PBP2a), a protein with low affinity for \u03b2-lactams that mediates cell wall assembly when the normal staphylococcal PBPs (PBP1 to -4) are blocked by these agents. Many MRSA strains display heterogeneous expression of resistance (HeR) against \u03b2-lactam antibiotics. The \u03b2-lactam-mediated homoresistant (HoR) phenotype is associated with both expression of the<jats:italic>mecA<\/jats:italic>gene and activation of the LexA-RecA-mediated SOS response, a regulatory network induced in response to DNA damage. Ceftaroline (CPT) is the only FDA-approved cephalosporin targeting PBP2a. We investigated the mechanistic basis of CPT activity against HeR-MRSA strains, including a set of strains displaying an intermediate level of resistance to CPT. Mechanistically, we found that 1 exposure of HeR-MRSA to subinhibitory concentrations of CPT selected for the HoR derivative activated the SOS response and increased mutagenesis. Importantly, CPT-selected HoR cells remained susceptible to CPT while still being resistant to most \u03b2-lactams, and 2-CPT activity in HeR-MRSA resided in an attenuated induction of<jats:italic>mecA<\/jats:italic>expression in comparison to other \u03b2-lactams. In addition, 3-CPT intermediate-resistant strains displayed a significant increase in CPT-induced<jats:italic>mecA<\/jats:italic>expression accompanied by mutations in PBP2, which together may interfere with the complete repression by CPT of both PBP2a and PBP2a-PBP2 interactions and thus be a determining factor in the low level of CPT resistance in the absence of<jats:italic>mecA<\/jats:italic>gene mutations. The present study provides mechanistic evidence that CPT represents an alternative therapeutic option for the treatment of heteroresistant MRSA strains.<\/jats:p>","DOI":"10.1128\/aac.03019-14","type":"journal-article","created":{"date-parts":[[2014,7,15]],"date-time":"2014-07-15T05:03:19Z","timestamp":1405400599000},"page":"5736-5746","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Ceftaroline Is Active against Heteroresistant Methicillin-Resistant Staphylococcus aureus Clinical Strains despite Associated Mutational Mechanisms and Intermediate Levels of Resistance"],"prefix":"10.1128","volume":"58","author":[{"given":"Regina","family":"Fernandez","sequence":"first","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana I.","family":"Paz","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto R.","family":"Rosato","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana E.","family":"Rosato","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA"},{"name":"Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.279.8.593"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.180.23.6077-6081.1998"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.183.22.6525-6531.2001"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04420.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.1.24-30.2002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.05176-0"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis559"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00330-12"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300118110"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja8029448"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00484-13"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01516-09"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkp164"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01119-09"},{"key":"e_1_3_2_16_2","volume-title":"Performance standards for antimicrobial disk susceptibility tests","author":"National Committee for Clinical Laboratory Standards","year":"2007","unstructured":"National Committee for Clinical Laboratory Standards. 2007. 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