
Two novel peptidoglycan hydrolases, PHAb10 and PHAb11, discovered from the Acinetobacter baumannii proteome exhibit potent bactericidal activity against a wide range of Gram-negative and Gram-positive pathogens, including multidrug-resistant strains, through a unique folding-refolding thermodynamic mechanism mediated by dimer-monomer transition.


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Phage-derived peptidoglycan hydrolases (i.e., lysins) are considered a promising alternative to traditional antibiotics due to their low risks of resistance and unique mechanisms of action. However, the discovery of these enzymes is often hampered by limited source of available phage genomes. Herein, we report a new strategy to mine novel peptidoglycan hydrolases from bacterial proteomes by lysin-derived antimicrobial peptide-primed screening. As a proof-of-concept, five novel peptidoglycan hydrolases from the Acinetobacter baumannii proteome (PHAb7-PHAb11) were identified using PlyF307 lysin-derived peptide as a template. PHAb10 and PHAb11 showed potent bactericidal activity against a variety of pathogens even after treatment at 100°C for 1 hour, while the other three were thermosensitive. We solved the crystal structures of PHAb8, PHAb10, and PHAb11 and unveiled that hyper-thermostable PHAb10 underwent a unique folding-refolding thermodynamic scheme mediated by the dimer-monomer transition, while thermosensitive PHAb8 formed a monomer. Two mouse models of bacterial infection further demonstrated the safety and efficacy of PHAb10. Altogether, our antimicrobial peptide-primed strategy provides new clues for the discovery of novel antimicrobial drugs with therapeutic promise.

### Competing Interest Statement

The authors have declared no competing interest.

Dimer-monomer transition defines a novel hyper-thermostable peptidoglycan hydrolase mined from bacterial proteome

thermostable-peptidoglycan-hydrolases-discovered-from-bacterial-proteome-exhibit-potent-bactericidal-activity-against-multidrug-resistant-pathogens


Thermostable Peptidoglycan Hydrolases Discovered from Bacterial Proteome Exhibit Potent Bactericidal Activity Against Multidrug-Resistant Pathogens
