Work

Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents

Year: 2024

Type: article

Abstract: 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 ( Sa ClpP) rather than Homo sapiens ClpP ( Hs ClpP) remains challenging. Herein, we rationally design and identify ZG297 by structure-based strategy. It binds and activates Sa ClpP instead of Hs ClpP. 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 antibiotic against multidrug-resistant S. aureus infections in Galleria mellonella larvae, zebrafish, murine skin, and thigh infection models. Collectively, we demonstrate that ZG297 is a safer and more potent antistaphylococcal agent than acyldepsipeptide 4 and ( R )-ZG197. • Structure-guided design yields selective Sa ClpP agonist ZG297 • Reversed “Tyr/His” pair in Sa ClpP and Hs ClpP is required for ZG297’s selectivity • ZG297 exhibits improved antistaphylococcal activity than ( R )-ZG197 • ZG297 is a safe and potent antibiotic for treating MRSA infections in vivo Zhang et al. identify a selective Sa ClpP agonist ZG297 that exhibits superior antistaphylococcal activities in vitro and in vivo . The reversed “tyrosine/histidine” pair in Sa ClpP and Hs ClpP is required for achieving selective activation on Sa ClpP. The study reports the development of selective and potent Sa ClpP agonists as antistaphylococcal agents.

Source: Cell Reports Medicine

DOI: 10.1016/j.xcrm.2024.101837