biostudies-literatureUnknown5(12)Zhang TMethicillin-resistant Staphylococcus aureus is a ubiquitous pathogen, posing a serious threat to human health worldwide. Thus, there is a high demand for antibiotics with distinct targets. Caseinolytic protease P (ClpP) is a promising target for combating staphylococcal infections; however, selectively activating S. aureus ClpP (SaClpP) rather than Homo sapiens ClpP (HsClpP) remains challenging. Herein, we rationally design and identify ZG297 by structure-based strategy. It binds and activates SaClpP instead of HsClpP. This is due to differentiated ligand binding attributed to crossed "tyrosine/histidine" amino acid pairs. ZG297 substantially inhibits the growth of a broad panel of S. aureus strains in vitro, outperforming the selective (R)-ZG197 agonist. ZG297 also functions as a potent aCell reports. Medicine101837https://www.ebi.ac.uk/biostudies/studies/S-EPMC11722091biostudies-literatureStructure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents.PMC11722091Zhang TWang PLi JWei BGan JLan LZhang MWu WZhou HYang CGZhao YfalseStructure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents.Methicillin-resistant Staphylococcus aureus is a ubiquitous pathogen, posing a serious threat to human health worldwide. Thus, there is a high demand for antibiotics with distinct targets. Caseinolytic protease P (ClpP) is a promising target for combating staphylococcal infections; however, selectively activating S. aureus ClpP (SaClpP) rather than Homo sapiens ClpP (HsClpP) remains challenging. Herein, we rationally design and identify ZG297 by structure-based strategy. It binds and activates SaClpP instead of HsClpP. This is due to differentiated ligand binding attributed to crossed "tyrosine/histidine" amino acid pairs. ZG297 substantially inhibits the growth of a broad panel of S. aureus strains in vitro, outperforming the selective (R)-ZG197 agonist. ZG297 also functions as a potent a2024-01-01T00:00:00Z2024 Dec2026-06-01T06:02:43.441Z2026-04-08T09:49:13.988ZS-EPMC117220913961548610.1016/j.xcrm.2024.101837