title: Insight into structure-function relationship in phenol-soluble modulins using an alanine screen of the phenol-soluble modulin (PSM) α3 peptide.
abstract: Phenol-soluble modulins (PSMs) are a family of peptides with multiple functions in staphylococcal pathogenesis. To gain insight into the structural features affecting PSM functions, we analyzed an alanine substitution library of PSMα3, a strongly cytolytic and proinflammatory PSM of Staphylococcus aureus with a significant contribution to S. aureus virulence. Lysine residues were essential for both receptor-dependent proinflammatory and receptor-independent cytolytic activities. Both phenotypes also required additional structural features, with the C terminus being crucial for receptor activation. Biofilm formation was affected mostly by hydrophobic amino acid positions, suggesting that the capacity to disrupt hydrophobic interactions is responsible for the effect of PSMs on biofilm structure. Antimicrobial activity, absent from natural PSMα3, could be created by the exchange of large hydrophobic side chains, indicating that PSMα3 has evolved to exhibit cytolytic rather than antimicrobial activity. In addition to gaining insight into the structure-function relationship in PSMs, our study identifies nontoxic PSMα3 derivatives for active vaccination strategies and lays the foundation for future efforts aimed to understand the biological role of PSM recognition by innate host defense.
authors.affiliation: 3National Institute of Allergy and Infectious Diseases, 9000 Rockville Pike, Bldg. 33 1W10, Bethesda, MD 20892, USA. motto@niaid.nih.gov.
authors.forename: Gordon Y C
authors.initials: GY
authors.lastname: Cheung
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kretschmer
authors.forename: Shu Y
authors.initials: SY
authors.lastname: Queck
authors.forename: Hwang-Soo
authors.initials: HS
authors.lastname: Joo
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Duong
authors.forename: Thuan H
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Thanh-Huy L
authors.initials: TH
authors.lastname: Bach
authors.forename: Adeline R
authors.initials: AR
authors.lastname: Porter
authors.forename: Frank R
authors.initials: FR
authors.lastname: DeLeo
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
mesh_terms: D000818:Animals; D018441:Biofilms; D002478:Cells, Cultured; D002942:Circular Dichroism; D005434:Flow Cytometry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010538:Peritonitis / Q000382:microbiology; D019800:Phenol / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity*; D013329:Structure-Activity Relationship; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D010455:Peptides; D037521:Virulence Factors; D019800:Phenol
keywords: Staphylococcus aureus; biofilm; hemolysis; inflammation; neutrophils; toxins