Structure-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 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.
Authors
- Bingyan Wei (ORCID: https://orcid.org/0000-0002-1782-0860)
- Cai‐Guang Yang (ORCID: https://orcid.org/0000-0001-5778-4422)
- Wenjuan Wu (ORCID: https://orcid.org/0000-0002-5161-3179)
- Jiahui Li (ORCID: https://orcid.org/0000-0002-9331-031X)
- Tao Zhang (ORCID: https://orcid.org/0000-0003-3287-4629)
- Jianhua Gan (ORCID: https://orcid.org/0000-0002-8438-8852)
- Lefu Lan (ORCID: https://orcid.org/0000-0002-5551-5496)
- Hailing Zhou
- Pengyu Wang (ORCID: https://orcid.org/0000-0002-4475-2381)
- Min Zhang (ORCID: https://orcid.org/0000-0002-4467-618X)
- Yanling Zhao (ORCID: https://orcid.org/0000-0003-1079-7896)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Shanghai Institute of Materia Medica (CN)
- Shanghai East Hospital (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101837
- Citations
- 5
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- National Natural Science Foundation of China
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- National Key Research and Development Program of China
- Youth Innovation Promotion Association