2. Academic Validation
  3. Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

  • Nat Commun. 2022 Nov 14;13(1):6909. doi: 10.1038/s41467-022-34753-0.
Bingyan Wei # 1 2 3,  Tao Zhang # 2,  Pengyu Wang # 1 2 3,  Yihui Pan 1 2 3,  Jiahui Li 2 3,  Weizhong Chen 4,  Min Zhang 5,  Quanjiang Ji 4,  Wenjuan Wu 5,  Lefu Lan 1 2 3,  Jianhua Gan 6,  Cai-Guang Yang 7 8 9
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 2 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5 Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
  • 6 School of Life Sciences, Fudan University, Shanghai, 200433, China.
  • 7 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. [email protected].
  • 8 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 9 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • # Contributed equally.
PMID: 36376309 DOI: 10.1038/s41467-022-34753-0
Abstract

The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more Antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of Bacterial ClpP is an alternative method of discovering Antibiotics, while it remains difficult to develop selective Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide Antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising Antibiotic efficacy in zebrafish and murine skin Infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.

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