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The agr locus in the commensal human pathogen, Staphylococcus aureus, is a two‐promoter regulon with allelic variability that produces a quorum‐sensing circuit involved in regulating virulence within the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentrations by AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. The finding that staphylococcal virulence can be inhibited through antagonism of this quorum‐sensing pathway has fueled tremendous interest in understanding the structure–activity relationships underlying the AIP–AgrC interaction. The defining structural feature of the AIP is a 16‐membered, thiolactone‐containing macrocycle. Surprisingly, the importance of ring size on agr activation or inhibition has not been explored. In this study, we address this deficiency through the …