title: Castanea sativa (European Chestnut) Leaf Extracts Rich in Ursene and Oleanene Derivatives Block Staphylococcus aureus Virulence and Pathogenesis without Detectable Resistance.
abstract: The Mediterranean is home to a rich history of medical traditions that have developed under the influence of diverse cultures over millennia. Today, many such traditions are still alive in the folk medical practices of local people. Investigation of botanical folk medicines used in the treatment of skin and soft tissue infections led us to study Castanea sativa (European Chestnut) for its potential antibacterial activity. Here, we report the quorum sensing inhibitory activity of refined and chemically characterized European Chestnut leaf extracts, rich in oleanene and ursene derivatives (pentacyclic triterpenes), against all Staphylococcus aureus accessory gene regulator (agr) alleles. We present layers of evidence of agr blocking activity (IC50 1.56-25 μg mL-1), as measured in toxin outputs, reporter assays hemolytic activity, cytotoxicity studies, and an in vivo abscess model. We demonstrate the extract's lack of cytotoxicity to human keratinocytes and murine skin, as well as lack of growth inhibitory activity against S. aureus and a panel of skin commensals. Lastly, we demonstrate that serial passaging of the extract does not result in acquisition of resistance to the quorum quenching composition. In conclusion, through disruption of quorum sensing in the absence of growth inhibition, this study provides insight into the role that non-biocide inhibitors of virulence may play in future antibiotic therapies.
authors: Center for the Study of Human Health, Emory University, Atlanta, Georgia, United States of America; Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Cassandra L
authors: CL
authors: Quave
authors: Center for the Study of Human Health, Emory University, Atlanta, Georgia, United States of America.
authors: James T
authors: JT
authors: Lyles
authors: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Jeffery S
authors: JS
authors: Kavanaugh
authors: Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Kate
authors: K
authors: Nelson
authors: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Corey P
authors: CP
authors: Parlet
authors: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Heidi A
authors: HA
authors: Crosby
authors: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Kristopher P
authors: KP
authors: Heilmann
authors: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Alexander R
authors: AR
authors: Horswill
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D024881:Drug Resistance, Bacterial; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D029962:Fagaceae / Q000737:chemistry*; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D009828:Oleanolic Acid / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry; D018515:Plant Leaves / Q000737:chemistry; D053038:Quorum Sensing / Q000187:drug effects*; D011817:Rabbits; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000187:drug effects
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D010936:Plant Extracts; D015534:Trans-Activators; C021091:staphylococcal alpha-toxin; C025971:staphylococcal delta toxin; D009828:Oleanolic Acid