Vijay S Gondil, Hailey S Butman, Mikaeel Young, Danica J Walsh, Yogesh Narkhede, Michael J Zeiler, Andrew H Crow, Morgan E Carpenter, Aashay Mardikar, Roberta J Melander, Olaf Wiest, Paul M Dunman, Christian Melander
Chemical biology & drug design 2024 JunStaphylococcus 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. © 2024 John Wiley & Sons Ltd.
Vijay S Gondil, Hailey S Butman, Mikaeel Young, Danica J Walsh, Yogesh Narkhede, Michael J Zeiler, Andrew H Crow, Morgan E Carpenter, Aashay Mardikar, Roberta J Melander, Olaf Wiest, Paul M Dunman, Christian Melander. Development of phenyl-urea-based small molecules that target penicillin-binding protein 4. Chemical biology & drug design. 2024 Jun;103(6):e14569
PMID: 38877369
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