ω-Hydroxyemodin limits staphylococcus aureus quorum sensing-mediated pathogenesis and inflammation

Area of Science:

• Microbiology
• Infectious Diseases
• Pharmacology

Background:

• Antibiotic-resistant pathogens pose a significant global health challenge.
• Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTIs) with increasing resistance.
• Bacterial virulence inhibitors offer a potential alternative or adjunct to traditional antibiotics.

Purpose of the Study:

• To investigate ω-hydroxyemodin (OHM) as a suppressor of Staphylococcus aureus quorum sensing (QS).
• To characterize the mechanism of OHM's anti-virulence activity.
• To evaluate OHM's efficacy in a preclinical model of S. aureus infection.

Main Methods:

• Identified OHM from Penicillium restrictum.
• Assessed OHM's effect on agr-mediated QS in S. aureus at non-toxic concentrations.
• Determined OHM's direct binding to the AgrA response regulator.
• Evaluated OHM in a mouse model of S. aureus SSTI.
• Assessed OHM's impact on bacterial clearance, inflammation, and host immune cell killing.

Main Results:

• OHM suppressed QS across all four S. aureus agr alleles at subinhibitory concentrations.
• OHM directly bound AgrA, inhibiting its interaction with the agr P2 promoter.
• OHM treatment reduced dermonecrosis, enhanced bacterial clearance, and decreased inflammatory cytokines in a mouse SSTI model.
• OHM improved S. aureus killing by immune cells in vitro in an agr-dependent manner.

Conclusions:

• OHM effectively disarms Staphylococcus aureus by suppressing QS.
• OHM bolsters the host innate immune response and mitigates inflammation.
• OHM represents a promising therapeutic strategy against antibiotic-resistant S. aureus infections.