Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence.
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.
Mayville
P
P
Laboratory of Synthetic Protein Chemistry, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Ji
G
G
Beavis
R
R
Yang
H
H
Goger
M
M
Novick
R P
RP
Muir
T W
TW
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