title: Virulence Inhibitors from Brazilian Peppertree Block Quorum Sensing and Abate Dermonecrosis in Skin Infection Models.
abstract: Widespread antibiotic resistance is on the rise and current therapies are becoming increasingly limited in both scope and efficacy. Methicillin-resistant Staphylococcus aureus (MRSA) represents a major contributor to this trend. Quorum sensing controlled virulence factors include secreted toxins responsible for extensive damage to host tissues and evasion of the immune system response; they are major contributors to morbidity and mortality. Investigation of botanical folk medicines for wounds and infections led us to study Schinus terebinthifolia (Brazilian Peppertree) as a potential source of virulence inhibitors. Here, we report the inhibitory activity of a flavone rich extract "430D-F5" against all S. aureus accessory gene regulator (agr) alleles in the absence of growth inhibition. Evidence for this activity is supported by its agr-quenching activity (IC502-32 μg mL-1) in transcriptional reporters, direct protein outputs (α-hemolysin and δ-toxin), and an in vivo skin challenge model. Importantly, 430D-F5 was well tolerated by human keratinocytes in cell culture and mouse skin in vivo; it also demonstrated significant reduction in dermonecrosis following skin challenge with a virulent strain of MRSA. This study provides an explanation for the anti-infective activity of peppertree remedies and yields insight into the potential utility of non-biocide virulence inhibitors in treating skin infections.
authors.affiliation: Center for the Study of Human Health, Emory University, 550 Asbury Circle, Candler Library 107E, Atlanta, Georgia, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Muhs
authors.affiliation: Center for the Study of Human Health, Emory University, 550 Asbury Circle, Candler Library 107E, Atlanta, Georgia, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Lyles
authors.affiliation: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Corey P
authors.initials: CP
authors.lastname: Parlet
authors.affiliation: Department of Dermatology, Emory University School of Medicine, 615 Michael St., Rm 105L WhiteheadBldg, Atlanta, GA, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Nelson
authors.affiliation: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Kavanaugh
authors.affiliation: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Horswill
authors.affiliation: Center for the Study of Human Health, Emory University, 550 Asbury Circle, Candler Library 107E, Atlanta, Georgia, USA.|Department of Dermatology, Emory University School of Medicine, 615 Michael St., Rm 105L WhiteheadBldg, Atlanta, GA, USA.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Quave
mesh_terms: D000483:Alleles; D027926:Anacardiaceae / Q000737:chemistry*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D004195:Disease Models, Animal; D006460:Hemolysin Proteins / Q000494:pharmacology; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D064307:Microbiota; D009336:Necrosis; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D053038:Quorum Sensing / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D012871:Skin Diseases / Q000382:microbiology / Q000473:pathology*; D018461:Soft Tissue Infections / Q000382:microbiology / Q000473:pathology; D014118:Toxins, Biological / Q000737:chemistry / Q000633:toxicity; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D006460:Hemolysin Proteins; D010936:Plant Extracts; D014118:Toxins, Biological