Fusion with a cell wall binding domain renders autolysin LytM a potent anti-Staphylococcus aureus agent

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Staphylococcus aureus is a major human pathogen causing significant morbidity and mortality.
• Existing therapeutics face challenges from drug-resistant strains, necessitating novel treatment strategies.
• Bacteriolytic enzymes, particularly phage lysins, show promise but endogenous enzymes are under-explored.

Purpose of the Study:

• To investigate the antibacterial potential of endogenous Staphylococcus aureus autolysins.
• To engineer the S. aureus autolysin LytM for enhanced bactericidal activity.
• To explore pathogen-derived enzymes as a novel source for antibacterial drug candidates.

Main Methods:

• Utilized the Staphylococcus aureus autolysin LytM as a model endogenous enzyme.
• Engineered a fusion protein combining LytM with the lysostaphin cell wall binding domain.
• Assessed the enhanced bactericidal activity of the engineered enzyme against S. aureus.

Main Results:

• Native LytM exhibited limited bactericidal activity.
• Fusion of LytM to the lysostaphin cell wall binding domain increased anti-staphylococcal activity by approximately 540-fold.
• The engineered enzyme demonstrated efficacy comparable to current phage lysins in preclinical development.

Conclusions:

• Endogenous peptidoglycan-degrading enzymes represent a promising, untapped reservoir for antibacterial drug discovery.
• Therapeutically co-opting pathogen's own enzymes offers a novel strategy against Staphylococcus aureus.
• Engineered LytM fusion proteins show potential as effective therapeutics against both drug-sensitive and drug-resistant S. aureus.