| Title: | "Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus" |
| Author(s): | Dowell M; Affas Z; Reynolds C; Holden MT; Wood SJ; Saint S; Cockayne A; Hill PJ; Dodd CE; Bycroft BW; Chan WC; Williams P; |
| Address: | "Institute of Infections and Immunity, School of Pharmaceutical Sciences, and School of BioSciences, University of Nottingham, Nottingham NG7 2RD, UK" |
| DOI: | 10.1046/j.1365-2958.2001.02539.x |
| ISSN/ISBN: | 0950-382X (Print) 0950-382X (Linking) |
| 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" |
| Keywords: | "Bacterial Proteins/*antagonists & inhibitors/metabolism Colony Count, Microbial Cyclization Electrophoresis, Polyacrylamide Gel *Evolution, Molecular *Gene Expression Regulation, Bacterial/drug effects Genes, Bacterial/genetics Genes, Reporter/genetics La;" |
| Notes: | "MedlineMDowell, P Affas, Z Reynolds, C Holden, M T Wood, S J Saint, S Cockayne, A Hill, P J Dodd, C E Bycroft, B W Chan, W C Williams, P eng Research Support, Non-U.S. Gov't England 2001/08/08 Mol Microbiol. 2001 Jul; 41(2):503-12. doi: 10.1046/j.1365-2958.2001.02539.x" |
