Quorum-sensing regulation in staphylococci-an overview

Abstract

Staphylococci are frequent human commensals and some species can cause disease. Staphylococcus aureus in particular is a dangerous human pathogen. In staphylococci, the ability to sense the bacterial cell density, or quorum, and to respond with genetic adaptations is due to one main system, which is called accessory gene regulator (Agr). The extracellular signal of Agr is a post-translationally modified peptide containing a thiolactone structure. Under conditions of high cell density, Agr is responsible for the increased expression of many toxins and degradative exoenzymes, and decreased expression of several colonization factors. This regulation is important for the timing of virulence factor expression during infection and the development of acute disease, while low activity of Agr is associated with chronic staphylococcal infections, such as those involving biofilm formation. Accordingly, drugs inhibiting Agr are being evaluated for their capacity to control acute forms of S. aureus infection.

Keywords: Agr; LuxS; Staphylococcus aureus; Staphylococcus epidermidis; biofilm; quorum-sensing; toxins.

Figure 1

Agr control in Staphylococcus. The quorum-sensing circuit is shown at the top left. The AIP signal is produced from the AgrD precursor by AgrB maturation and export. At a certain threshold concentration, AIP activates the AgrC-AgrA two-component system and phosphorylated AgrA activates transcription from the P2 promoter, resulting in auto-feedback regulation. An important feature of Agr is group specificity, resulting in cross-inhibition, i.e., inhibition of Agr activity, in strains belonging to other Agr specificity groups and other species (top right). Target gene control is shown at the bottom. Most Agr targets are regulated via RNAIII, whose transcription is increased by AgrA, via the P3 promoter. RNAIII also contains the gene for delta-toxin (hld). RNAIII controls target genes by base pairing with 5′UTRs, in most cases inhibiting translation. This is used for direct inhibition of Agr-inhibited target genes such as protein A, while inhibition of translation of the repressor Rot leads to de-repression of transcription of many of the classical Agr target toxins, such as alpha-toxin. AgrA also increases transcription of the psmα and psmβ operons, encoding PSM peptides, in an RNAIII-independent mode of Agr target gene regulation. S.D., Shine/Dalgarno sequence; AUG, start codon of controlled gene.