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

Summary

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 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.

Graphical abstract

Highlights

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  Structure-guided design yields selective SaClpP agonist ZG297

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  Reversed “Tyr/His” pair in SaClpP and HsClpP is required for ZG297’s selectivity

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  ZG297 exhibits improved antistaphylococcal activity than ( R)-ZG197

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  ZG297 is a safe and potent antibiotic for treating MRSA infections in vivo

Abstract

Zhang et al. identify a selective SaClpP agonist ZG297 that exhibits superior antistaphylococcal activities in vitro and in vivo. The reversed “tyrosine/histidine” pair in SaClpP and HsClpP is required for achieving selective activation on SaClpP. The study reports the development of selective and potent SaClpP agonists as antistaphylococcal agents.