title: Role of Phenol-Soluble Modulins in Formation of Staphylococcus aureus Biofilms in Synovial Fluid.
abstract: Staphylococcus aureus is a leading cause of prosthetic joint infections, which, as we recently showed, proceed with the involvement of biofilm-like clusters that cause recalcitrance to antibiotic treatment. Here we analyzed why these clusters grow extraordinarily large, reaching macroscopically visible extensions (>1 mm). We found that while specific S. aureus surface proteins are a prerequisite for agglomeration in synovial fluid, low activity of the Agr regulatory system and subsequent low production of the phenol-soluble modulin (PSM) surfactant peptides cause agglomerates to grow to exceptional dimensions. Our results indicate that PSMs function by disrupting interactions of biofilm matrix molecules, such as the polysaccharide intercellular adhesin (PIA), with the bacterial cell surface. Together, our findings support a two-step model of staphylococcal prosthetic joint infection: As we previously reported, interaction of S. aureus surface proteins with host matrix proteins such as fibrin initiates agglomeration; our present results show that, thereafter, the bacterial agglomerates grow to extremely large sizes owing to the lack of PSM expression under the specific conditions present in joints. Our findings provide a mechanistic explanation for the reported extreme resistance of joint infection to antibiotic treatment, lend support to the notions that Agr functionality and PSM production play a major role in defining different forms of S. aureus infection, and have important implications for antistaphylococcal therapeutic strategies.
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Sana S
authors.initials: SS
authors.lastname: Dastgheyb
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Amer E
authors.initials: AE
authors.lastname: Villaruz
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Katherine Y
authors.initials: KY
authors.lastname: Le
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Vee Y
authors.initials: VY
authors.lastname: Tan
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Duong
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Som S
authors.initials: SS
authors.lastname: Chatterjee
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gordon Y C
authors.initials: GY
authors.lastname: Cheung
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Hwang-Soo
authors.initials: HS
authors.lastname: Joo
authors.affiliation: Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Noreen J
authors.initials: NJ
authors.lastname: Hickok
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA motto@niaid.nih.gov.
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism*; D018441:Biofilms / Q000254:growth & development*; D006801:Humans; D016459:Prosthesis-Related Infections / Q000382:microbiology; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000378:metabolism / Q000502:physiology*; D013501:Surface-Active Agents / Q000378:metabolism; D013582:Synovial Fluid / Q000382:microbiology*
chemical_list: D001427:Bacterial Toxins; D013501:Surface-Active Agents; C025971:staphylococcal delta toxin