title: Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence.
abstract: The synthesis of virulence factors and other extracellular proteins responsible for pathogenicity in Staphylococcus aureus is under the control of the agr locus. A secreted agr-encoded peptide, AgrD, processed from the AgrD gene product, is known to be an effector of self-strain activation and cross-strain inhibition of the agr response. Biochemical analysis of AgrD peptides isolated from culture supernatants has suggested that they contain an unusual thiol ester-linked cyclic structure. In the present work, chemical synthesis is used to confirm that the mature AgrD peptides contain a thiolactone structure and that this feature is absolutely necessary for full biological activity. The AgrD synthetic thiolactone peptides exhibited biological activity in vivo in a mouse protection test. Structure-activity studies have allowed key aspects of the peptide structure involved in the differential activation and inhibition functions to be identified. Accordingly, we propose a model for activation and inhibition of the agr response in which the former, but not the latter, involves specific acylation of the agr transmembrane receptor, AgrC.
authors.affiliation: Laboratory of Synthetic Protein Chemistry, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
authors.forename: P
authors.initials: P
authors.lastname: Mayville
authors.forename: G
authors.initials: G
authors.lastname: Ji
authors.forename: R
authors.initials: R
authors.lastname: Beavis
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Goger
authors.forename: R P
authors.initials: RP
authors.lastname: Novick
authors.forename: T W
authors.initials: TW
authors.lastname: Muir
mesh_terms: D000038:Abscess / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D007769:Lactams; D007783:Lactones / Q000737:chemistry; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017192:Skin Diseases, Bacterial / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D014774:Virulence / Q000235:genetics