2. Academic Validation
  3. Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents

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

  • Cell Rep Med. 2024 Dec 17;5(12):101837. doi: 10.1016/j.xcrm.2024.101837.
Tao Zhang 1,  Pengyu Wang 2,  Hailing Zhou 3,  Bingyan Wei 2,  Yanling Zhao 4,  Jiahui Li 1,  Min Zhang 5,  Wenjuan Wu 5,  Lefu Lan 6,  Jianhua Gan 7,  Cai-Guang Yang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 3 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5 Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7 School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 8 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China. Electronic address: yangcg@simm.ac.cn.
PMID: 39615486 DOI: 10.1016/j.xcrm.2024.101837
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 (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.

Keywords

ClpP; MRSA; ZG297; antibiotic; antistaphylococcal agents; caseinolytic protease P; methicillin-resistant Staphylococcus aureus; murine skin infection model; murine thigh infection model; selective agonist; structure guided design; tyrosine/histidine pairs.

Figures
Products