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

Mol Microbiol. 2001 Jul;41(2):503-12. doi: 10.1046/j.1365-2958.2001.02539.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Colony Count, Microbial
  • Cyclization
  • Electrophoresis, Polyacrylamide Gel
  • Evolution, Molecular*
  • Gene Expression Regulation, Bacterial* / drug effects
  • Genes, Bacterial / genetics
  • Genes, Reporter / genetics
  • Lactams / chemical synthesis
  • Lactams / chemistry
  • Lactams / metabolism
  • Lactams / pharmacology
  • Molecular Sequence Data
  • Molecular Structure
  • Oligopeptides / chemistry
  • Oligopeptides / genetics
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Oxidation-Reduction
  • Phenotype
  • Pheromones / chemistry*
  • Pheromones / genetics
  • Pheromones / metabolism*
  • Pheromones / pharmacology
  • RNA, Bacterial / genetics
  • RNA, Bacterial / metabolism
  • Signal Transduction* / drug effects
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / metabolism*
  • Staphylococcus aureus / pathogenicity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / metabolism
  • Virulence / genetics

Substances

  • Agr protein, Staphylococcus aureus
  • Bacterial Proteins
  • Lactams
  • Oligopeptides
  • Pheromones
  • RNA, Bacterial
  • Trans-Activators

Associated data

  • GENBANK/AF001782
  • GENBANK/AF001783