Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus

P McDowell, Z Affas, C Reynolds, MTG Holden, SJ Wood, S Saint, A Cockayne, PJ Hill, CER Dodd, BW Bycroft, WC Chan, P Williams*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

142 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)503-512
Number of pages10
JournalMolecular Microbiology
Volume41
Issue number2
Publication statusPublished - Jul 2001

Keywords

  • GENE REGULATOR AGR
  • STREPTOCOCCUS-PNEUMONIAE
  • METHIONINE SULFOXIDE
  • AMINO-ACIDS
  • VIRULENCE
  • PHEROMONE
  • COMPETENCE
  • MODEL
  • TRANSFORMATION
  • AUTOINDUCER

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