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Abstract Staphylococcus aureusis a ubiquitous bacterium that has become a major threat to human health due to its extensive toxin production and tremendous capacity for antibiotic resistance (e. g., MRSA “superbug” infections). Amid a worsening antibiotic resistance crisis, new strategies to combat this deadly microbe that remove the selective pressure of traditional approaches are in high demand.S. aureusutilizes an accessory gene regulator (agr) quorum sensing network to monitor its local cellular population and trigger a devastating communal attack, like an invading horde, once a threshold cell density has been reached. The role of theagrsystem in a range of disease types is still being unraveled. Herein, we discuss the present‐day biochemical understanding ofagralong with unresolved details, describe its connection to the progression of infection, and review how chemical strategies have been implemented to study and intercept this signaling pathway. This research is illuminating the potential ofagras an anti‐virulence target inS. aureusand should inform the study of similar, yet less studied,agrsystems in related bacterial pathogens. 

Staphylococcus aureus uses small peptides to assess its population densisty ( i.e. , quorum sensing) and regulate virulence at high cell number. Here, we report the design and synthesis of peptidomimetics based on these native signals that strongly block this communication pathway in all four specificity groups of S. aureus .