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
  • 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: [email protected].
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.
Products