title: Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus.
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.
authors.affiliation: Institute of Infections and Immunity, School of Pharmaceutical Sciences, and School of BioSciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: P
authors.initials: P
authors.lastname: MDowell
authors.forename: Z
authors.initials: Z
authors.lastname: Affas
authors.forename: C
authors.initials: C
authors.lastname: Reynolds
authors.forename: M T
authors.initials: MT
authors.lastname: Holden
authors.forename: S J
authors.initials: SJ
authors.lastname: Wood
authors.forename: S
authors.initials: S
authors.lastname: Saint
authors.forename: A
authors.initials: A
authors.lastname: Cockayne
authors.forename: P J
authors.initials: PJ
authors.lastname: Hill
authors.forename: C E
authors.initials: CE
authors.lastname: Dodd
authors.forename: B W
authors.initials: BW
authors.lastname: Bycroft
authors.forename: W C
authors.initials: WC
authors.lastname: Chan
authors.forename: P
authors.initials: P
authors.lastname: Williams
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015169:Colony Count, Microbial; D003500:Cyclization; D004591:Electrophoresis, Polyacrylamide Gel; D019143:Evolution, Molecular; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D010641:Phenotype; D010675:Pheromones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012329:RNA, Bacterial / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014774:Virulence / Q000235:genetics
chemical_list: C095698:Agr protein, Staphylococcus aureus; D001426:Bacterial Proteins; D007769:Lactams; D009842:Oligopeptides; D010675:Pheromones; D012329:RNA, Bacterial; D015534:Trans-Activators