Rational design of a global inhibitor of the virulence response in Staphylococcus aureus, based in part on localization of the site of inhibition to the receptor-histidine kinase, AgrC

Two-component signaling systems involving receptor-histidine kinases are ub iquitous in bacteria and have been found in yeast and plants. These systems provide the major means by which bacteria communicate with each other and the outside world. Remarkably, very little is known concerning the extracel lular ligands that presumably bind to receptor-histidine kinases to initiat e signaling. The two-component agr signaling circuit in Staphylococcus aure us is one system where the ligands are known in chemical detail, thus openi ng the door for detailed structure-activity relationship studies. These lig ands are short (8- to 9-aa) peptides containing a thiolactone structure, in which the alpha -carboxyl group of the C-terminal amino acid is linked to the sulfhydryl group of a cysteine, which is always the fifth amino acid fr om the C terminus of the peptide. One unique aspect of the agr system is th at peptides that activate virulence expression in one group of S. aureus st rains also inhibit virulence expression in other groups of S. aureus strain s. Herein, it is demonstrated by switching the receptor-histidine kinase, A grC, between strains of different agr specificity types, that intragroup ac tivation and intergroup inhibition are both mediated by the same group-spec ific receptors. These results have facilitated the development of a global inhibitor of virulence in S. aureus, which consists of a truncated version of one of the naturally occurring thiolactone peptides.