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J Med Chem. 2019 Oct 28. doi: 10.1021/acs.jmedchem.9b00798. [Epub ahead of print]

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

Abstract

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 upregulate 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 anti-virulence 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. Based on 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.

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