Structure-activity analysis of synthetic autoinducing thiolactone peptidesfrom Staphylococcus aureus responsible for virulence

The synthesis of virulence factors and other extracellular proteins respons ible for pathogenicity in Staphylococcus aureus is under the control of the agr locus. A secreted agr-encoded peptide, AgrD, processed from the AgrD g ene product, is known to be an effector of self-strain activation and cross -strain inhibition of the agr response. Biochemical analysis of AgrD peptid es isolated from culture supernatants has suggested that they contain an un usual thiol ester-linked cyclic structure. In the present work, chemical sy nthesis is used to confirm that the mature AgrD peptides contain a thiolact one structure and that this feature is absolutely necessary for full biolog ical activity. The AgrD synthetic thiolactone peptides exhibited biological activity in vivo in a mouse protection test. Structure-activity studies ha ve allowed key aspects of the peptide structure involved in the differentia l activation and inhibition functions to be identified. Accordingly, we pro pose a model far activation and inhibition of the agr response in which the former, but not the latter, Involves specific acylation of the agr transme mbrane receptor, AgrC.