†Present address: The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridge C10 1SA, UK.
Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus
Article first published online: 21 DEC 2001
Volume 41, Issue 2, pages 503–512, July 2001
How to Cite
MDowell, P., Affas, Z., Reynolds, C., Holden, M. T. G., Wood, S. J., Saint, S., Cockayne, A., Hill, P. J., Dodd, C. E. R., Bycroft, B. W., Chan, W. C. and Williams, P. (2001), Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus. Molecular Microbiology, 41: 503–512. doi: 10.1046/j.1365-2958.2001.02539.x
- Issue published online: 21 DEC 2001
- Article first published online: 21 DEC 2001
- Accepted 14 May, 2001.
In Staphylococcus aureus, the agr locus is responsible for controlling virulence gene expression via quorum sensing. As the blockade of quorum sensing offers a novel strategy for attenuating infection, we sought to gain novel insights into the structure, activity and turnover of the secreted staphylococcal autoinducing peptide (AIP) signal molecules. A series of analogues (including the l-alanine and d-amino acid scanned peptides) was synthesized to determine the functionally critical residues within the S. aureus group I AIP. As a consequence, we established that (i) the group I AIP is inactivated in culture supernatants by the formation of the corresponding methionyl sulphoxide; and (ii) the group I AIP lactam analogue retains the capacity to activate agr, suggesting that covalent modification of the AgrC receptor is not a necessary prerequisite for agr activation. Although each of the d-amino acid scanned AIP analogues retained activity, replacement of the endocyclic amino acid residue (aspartate) located C-terminally to the central cysteine with alanine converted the group I AIP from an activator to a potent inhibitor. The screening of clinical S. aureus isolates for novel AIP groups revealed a variant that differed from the group I AIP by a single amino acid residue (aspartate to tyrosine) in the same position defined as critical by alanine scanning. Although this AIP inhibits group I S. aureus strains, the producer strains possess a functional agr locus dependent on the endogenous peptide and, as such, constitute a fourth S. aureus AIP pheromone group (group IV). The addition of exogenous synthetic AIPs to S. aureus inhibited the production of toxic shock syndrome toxin (TSST-1) and enterotoxin C3, confirming the potential of quorum-sensing blockade as a therapeutic strategy.