n-(3-oxododecanoyl)homoserine-lactone and Staphylococcal-Infections

A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Cell Line; Furans; Indicators and Reagents; Iron Chelating Agents; Mice; Microbial Sensitivity Tests; Nasal Cavity; Peptides, Cyclic; Protein Kinases; Pyrrolidinones; Quorum Sensing; Signal Transduction; Small Molecule Libraries; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship

Virulence gene expression in Staphylococcus aureus is tightly regulated by intricate networks of transcriptional regulators and two-component signal transduction systems. There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models. In this Perspective, we will provide insights into medicinal chemistry strategies for the development of chemical reagents that have the capacity to inhibit staphylococcal virulence expression. These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA-DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators. We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections.

Topics: Anti-Bacterial Agents; Bacterial Proteins; DNA; Genes, Bacterial; Peptides, Cyclic; Quorum Sensing; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Trans-Activators; Virulence; Virulence Factors