ω-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

Abstract

ABSTRACTAntibiotic-resistant pathogens are a global health threat. Small molecules that inhibit bacterial virulence have been suggested as alternatives or adjuncts to conventional antibiotics, as they may limit pathogenesis and increase bacterial susceptibility to host killing.Staphylococcus aureusis a major cause of invasive skin and soft tissue infections (SSTIs) in both the hospital and community settings, and it is also becoming increasingly antibiotic resistant. Quorum sensing (QS) mediated by the accessory gene regulator (agr) controls virulence factor production essential for causing SSTIs. We recently identified ω-hydroxyemodin (OHM), a polyhydroxyanthraquinone isolated from solid-phase cultures ofPenicillium restrictum, as a suppressor of QS and a compound sought for the further characterization of the mechanism of action. At concentrations that are nontoxic to eukaryotic cells and subinhibitory to bacterial growth, OHM preventedagrsignaling by all fourS. aureus agralleles. OHM inhibited QS by direct binding to AgrA, the response regulator encoded by theagroperon, preventing the interaction of AgrA with theagrP2 promoter. Importantly, OHM was efficacious in a mouse model ofS. aureusSSTI. Decreased dermonecrosis with OHM treatment was associated with enhanced bacterial clearance and reductions in inflammatory cytokine transcription and expression at the site of infection. Furthermore, OHM treatment enhanced the immune cell killing ofS. aureusin vitroin anagr-dependent manner. These data suggest that bacterial disarmament through the suppression ofS. aureusQS may bolster the host innate immune response and limit inflammation.