{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:49:53Z","timestamp":1792705793402,"version":"4.5.0"},"reference-count":49,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P50 AR072000"],"award-info":[{"award-number":["P50 AR072000"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 AI134685"],"award-info":[{"award-number":["R01 AI134685"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P30 AR069655"],"award-info":[{"award-number":["P30 AR069655"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R21 AR081050"],"award-info":[{"award-number":["R21 AR081050"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01DE022350"],"award-info":[{"award-number":["R01DE022350"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Methicillin-resistant Staphylococcus aureus (MRSA) is a global healthcare concern. Such resistance has historically been attributed to the acquisition of mecA (or mecC), which encodes an alternative penicillin binding protein, PBP2a, with low \u03b2-lactam affinity. However, recent studies have indicated that penicillin binding protein 4 (PBP4) is also a critical determinant of S. aureus methicillin resistance, particularly among community-acquired MRSA strains. Thus, PBP4 has been considered an intriguing therapeutic target as corresponding inhibitors may restore MRSA \u03b2-lactam susceptibility. In addition to its role in antibiotic resistance, PBP4 has also recently been shown to be required for S. aureus cortical bone osteocyte lacuno-canalicular network (OLCN) invasion and colonization, providing the organism with a niche for re-occurring bone infection. From these perspectives, the development of PBP4 inhibitors may have tremendous impact as agents that both reverse methicillin resistance and inhibit the organism\u2019s ability to cause chronic osteomyelitis. Accordingly, using a whole-cell high-throughput screen of a 30,000-member small molecule chemical library and secondary assays we identified putative S. aureus PBP4 inhibitors. Quantitative reverse transcriptase mediated PCR and PBP4 binding assays revealed that hits could be further distinguished as compounds that reduce PBP4 expression versus compounds that are likely to affect the protein\u2019s function. We also showed that 6.25 \u00b5M (2.5 \u00b5g\/mL) of the lead candidate, 9314848, reverses the organism\u2019s PBP4-dependent MRSA phenotype and inhibits its ability to traverse Microfluidic-Silicon Membrane-Canalicular Arrays (\u00b5SiM-CA) that model the OLCN orifice. Collectively, these molecules may represent promising potential as PBP4-inhibitors that can be further developed as adjuvants for the treatment of MRSA infections and\/or osteomyelitis prophylactics.<\/jats:p>","DOI":"10.3390\/antibiotics11101351","type":"journal-article","created":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T22:47:27Z","timestamp":1665182847000},"page":"1351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identification of Staphylococcus aureus Penicillin Binding Protein 4 (PBP4) Inhibitors"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-4111","authenticated-orcid":false,"given":"Mikaeel","family":"Young","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danica J.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elysia","family":"Masters","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5603-7345","authenticated-orcid":false,"given":"Vijay Singh","family":"Gondil","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Laskey","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0478-0561","authenticated-orcid":false,"given":"Michael","family":"Klaczko","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2197-2610","authenticated-orcid":false,"given":"Hani","family":"Awad","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA"},{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"McGrath","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4854-9698","authenticated-orcid":false,"given":"Edward M.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"},{"name":"Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA"},{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Melander","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Dunman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nrmicro2200","article-title":"Waves of resistance: Staphylococcus aureus in the antibiotic era","volume":"7","author":"Chambers","year":"2009","journal-title":"Nat. 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