title: Solonamide B inhibits quorum sensing and reduces Staphylococcus aureus mediated killing of human neutrophils.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and particularly the spread of community associated (CA)-MRSA strains such as USA300 is a concern, as these strains can cause severe infections in otherwise healthy adults. Recently, we reported that a cyclodepsipeptide termed Solonamide B isolated from the marine bacterium, Photobacterium halotolerans strongly reduces expression of RNAIII, the effector molecule of the agr quorum sensing system. Here we show that Solonamide B interferes with the binding of S. aureus autoinducing peptides (AIPs) to sensor histidine kinase, AgrC, of the agr two-component system. The hypervirulence of USA300 has been linked to increased expression of central virulence factors like α-hemolysin and the phenol soluble modulins (PSMs). Importantly, in strain USA300 Solonamide B dramatically reduced the activity of α-hemolysin and the transcription of psma encoding PSMs with an 80% reduction in toxicity of supernatants towards human neutrophils and rabbit erythrocytes. To our knowledge this is the first report of a compound produced naturally by a Gram-negative marine bacterium that interferes with agr and affects both RNAIII and AgrA controlled virulence gene expression in S. aureus.
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anita
authors.initials: A
authors.lastname: Nielsen
authors.affiliation: Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Månsson
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Bojer
authors.affiliation: Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Lone
authors.initials: L
authors.lastname: Gram
authors.affiliation: Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Larsen
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Novick
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Frees
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Frøkiær
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Ingmer
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D009504:Neutrophils / Q000187:drug effects / Q000382:microbiology*; D010456:Peptides, Cyclic / Q000302:isolation & purification / Q000494:pharmacology*; D010776:Photobacterium / Q000737:chemistry; D061251:Primary Cell Culture; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects* / Q000235:genetics; D011817:Rabbits; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014774:Virulence
chemical_list: C095698:Agr protein, Staphylococcus aureus; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D010456:Peptides, Cyclic; D015534:Trans-Activators; C558621:solomonamide B; C021091:staphylococcal alpha-toxin; C025971:staphylococcal delta toxin; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus