Structure-Activity Relationship Studies of Small Molecule Modulators of the Staphylococcal Accessory Gene Regulator

J Med Chem. 2020 Mar 26;63(6):2705-2730. doi: 10.1021/acs.jmedchem.9b00798. Epub 2019 Nov 14.


The accessory gene regulator (agr) quorum-sensing system is arguably the most important regulator of Staphylococcus virulence. The agr-system serves a crucial role in pathogenesis by triggering substantive gene expression alterations to up-regulate the production of a wide variety of virulence determinants such as exoenzymes (proteases, lipases, nucleases) and downregulate the expression of surface binding proteins. Accordingly, the agr-system represents a compelling target for the development of antivirulence therapeutics as potential adjuncts, or alternatives, to conventional bactericidal and bacteriostatic antibiotics. Despite this potential, to date, no agr-system inhibitors have progressed to the clinic; however, several promising lead compounds have been identified through screens of synthetic and natural product libraries. On the basis of the molecular components within the agr-system, the current contingent of regulating compounds can be clustered into three broad groups, AgrA-P3 activation inhibitors, AgrB-AgrD processing inhibitors, and AgrC-AIP interaction inhibitors. This review aims to provide an overview of the development, structure-activity-relationships, and limitations of compounds within each of these groups in addition to the current opportunities for developing next-generation anologs.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Drug Discovery / methods
  • Humans
  • Models, Molecular
  • Quorum Sensing / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology
  • Staphylococcus / drug effects*
  • Staphylococcus / physiology
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / physiology
  • Structure-Activity Relationship
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / metabolism


  • Agr protein, Staphylococcus aureus
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Small Molecule Libraries
  • Trans-Activators