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It was recently established that the cell wall transpeptidase, penicillin\u2010binding protein 4 (PBP4), is crucial for this function, with <jats:italic>pbp4<\/jats:italic> deletion strains unable to invade OLCNs and cause bone pathogenesis in a murine model of <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic> osteomyelitis. Moreover, PBP4 has recently been found to modulate <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic> resistance to \u03b2\u2010lactam antibiotics. As such, small molecule inhibitors of <jats:italic>S<\/jats:italic>. <jats:italic>aureus<\/jats:italic> PBP4 may represent dual functional antimicrobial agents that limit osteomyelitis and\/or reverse antibiotic resistance. A high throughput screen recently revealed that the phenyl\u2010urea <jats:bold>1<\/jats:bold> targets PBP4. Herein, we describe a structure\u2013activity relationship (SAR) study on <jats:bold>1.<\/jats:bold> Leveraging in silico docking and modeling, a set of analogs was synthesized and assessed for PBP4 inhibitory activities. Results revealed a preliminary SAR and identified lead compounds with enhanced binding to PBP4, more potent antibiotic resistance reversal, and diminished PBP4 cell wall transpeptidase activity in comparison to <jats:bold>1<\/jats:bold>.<\/jats:p>","DOI":"10.1111\/cbdd.14569","type":"journal-article","created":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T03:07:10Z","timestamp":1718420830000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Development of phenyl\u2010urea\u2010based small molecules that target penicillin\u2010binding protein 4"],"prefix":"10.1111","volume":"103","author":[{"given":"Vijay S.","family":"Gondil","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology University of Rochester Medical Center  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey 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