PUBLICATION
Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
- Authors
- Wei, B., Zhang, T., Wang, P., Pan, Y., Li, J., Chen, W., Zhang, M., Ji, Q., Wu, W., Lan, L., Gan, J., Yang, C.G.
- ID
- ZDB-PUB-221116-1
- Date
- 2022
- Source
- Nature communications 13: 6909 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/chemistry
- Anti-Bacterial Agents/pharmacology
- Anti-Bacterial Agents/therapeutic use
- Endopeptidase Clp/metabolism
- Methicillin-Resistant Staphylococcus aureus*/metabolism
- Mice
- Microbial Sensitivity Tests
- Staphylococcal Infections*/drug therapy
- Staphylococcal Infections*/microbiology
- Staphylococcus aureus/metabolism
- Zebrafish/metabolism
- PubMed
- 36376309 Full text @ Nat. Commun.
Citation
Wei, B., Zhang, T., Wang, P., Pan, Y., Li, J., Chen, W., Zhang, M., Ji, Q., Wu, W., Lan, L., Gan, J., Yang, C.G. (2022) Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP. Nature communications. 13:6909.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping