{"doi":"10.1111/cbdd.14569","title":"Development of phenyl‐urea‐based small molecules that target penicillin‐binding protein 4","abstract":"Staphylococcus aureus has the ability to invade cortical bone osteocyte lacuno-canalicular networks (OLCNs) and cause osteomyelitis. It was recently established that the cell wall transpeptidase, penicillin-binding protein 4 (PBP4), is crucial for this function, with pbp4 deletion strains unable to invade OLCNs and cause bone pathogenesis in a murine model of S. aureus osteomyelitis. Moreover, PBP4 has recently been found to modulate S. aureus resistance to β-lactam antibiotics. As such, small molecule inhibitors of S. aureus PBP4 may represent dual functional antimicrobial agents that limit osteomyelitis and/or reverse antibiotic resistance. A high throughput screen recently revealed that the phenyl-urea 1 targets PBP4. Herein, we describe a structure-activity relationship (SAR) study on 1. 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 1.","journal":"Chemical Biology & Drug Design","year":2024,"id":448796,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":474098,"name":"Hailey S. Butman","orcid":null,"position":1,"is_corresponding":false},{"id":690828,"name":"Mikaeel Young","orcid":"0000-0003-1666-4111","position":2,"is_corresponding":false},{"id":880873,"name":"Danica J. Walsh","orcid":"0000-0002-5509-1224","position":3,"is_corresponding":false},{"id":316868,"name":"Yogesh B. Narkhede","orcid":"0000-0003-4358-2912","position":4,"is_corresponding":false},{"id":416563,"name":"Michael J. Zeiler","orcid":"0009-0001-0454-342X","position":5,"is_corresponding":false},{"id":1268177,"name":"Andrew H. Crow","orcid":null,"position":6,"is_corresponding":false},{"id":966200,"name":"Morgan E. Carpenter","orcid":null,"position":7,"is_corresponding":false},{"id":1267726,"name":"Aashay Mardikar","orcid":"0000-0002-7168-3764","position":8,"is_corresponding":false},{"id":517532,"name":"Roberta J. Melander","orcid":"0000-0002-3548-3351","position":9,"is_corresponding":false},{"id":397450,"name":"Olaf Wiest","orcid":"0000-0001-9316-7720","position":10,"is_corresponding":false},{"id":451547,"name":"Paul M. Dunman","orcid":"0000-0001-5138-521X","position":11,"is_corresponding":false},{"id":258371,"name":"Christian Melander","orcid":"0000-0001-8271-4696","position":12,"is_corresponding":false},{"id":880874,"name":"Vijay Singh Gondil","orcid":"0000-0001-5603-7345","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:02:12.215092Z","pmid":"38877369","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}