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Review
. 2013 Apr 18;13(4):5130-66.
doi: 10.3390/s130405130.

Targeting agr- and agr-Like quorum sensing systems for development of common therapeutics to treat multiple gram-positive bacterial infections

Brian Gray  1 , Pamela Hall, Hattie Gresham
Affiliations
Review

Targeting agr- and agr-Like quorum sensing systems for development of common therapeutics to treat multiple gram-positive bacterial infections

Brian Gray et al. Sensors (Basel). .

Abstract

Invasive infection by the Gram-positive pathogen Staphylococcus aureus is controlled by a four gene operon, agr that encodes a quorum sensing system for the regulation of virulence. While agr has been well studied in S. aureus, the contribution of agr homologues and analogues in other Gram-positive pathogens is just beginning to be understood. Intriguingly, other significant human pathogens, including Clostridium perfringens, Listeria monocytogenes, and Enterococcus faecalis contain agr or analogues linked to virulence. Moreover, other significant human Gram-positive pathogens use peptide based quorum sensing systems to establish or maintain infection. The potential for commonality in aspects of these signaling systems across different species raises the prospect of identifying therapeutics that could target multiple pathogens. Here, we review the status of research into these agr homologues, analogues, and other peptide based quorum sensing systems in Gram-positive pathogens as well as the potential for identifying common pathways and signaling mechanisms for therapeutic discovery.

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Figures

Figure 1.
Figure 1.
The structure and function of the agr operon in S. aureus. AgrB is a multifunctional endopeptidase and chaperone protein, and it has been suggested that AgrB is also involved in the export of AIP. AgrD is a propeptide processed by AgrB into the small thiolactone AIP. AgrC is the integral membrane sensor part of a two-component regulatory system. AgrA is the transcription factor response regulator companion to AgrC, and acts on the divergent P2/P3 promoter to upregulate agr and RNAIII expression, in addition to several other transcriptional targets. The regulatory RNA molecule RNAIII acts on numerous gene transcripts to modulate gene expression through post-transcriptional control.
Figure 2.
Figure 2.
Structures of thiolactone and lactone signal peptides. (a) Structure of the prototypical autoinducing peptide, S. aureus AIP-1. (b) AIP-1 from S. pseudintermedius, the only reported Staphylococcus species with a lactone autoinducing molecule. (c) Gelatinase biosynthesis activating peptide (GBAP) from Enterococcus faecalis.
Figure 3.
Figure 3.
Known targets in agr-homologues and other peptide quormone QS systems with the potential for chemotherapeutic intervention to inhibit or retard virulence. Colored dots indicate which species are reported to possess agr homologues or analogues at the indicated step. (1) Binding and C′ terminal cleavage of AgrD/propeptide by AgrB/endopeptidase. (2) Cyclization of cleaved propeptide by AgrB. (3) Export of partially formed AIP/signal peptide by endopeptidase/export channel. (4) Binding of AIP by AgrC/cognate receptor module. (5) Dimerization and/or activation of the AgrC/receptor module HPK. (6) Phosphorylation and activation of AgrA/regulatory module by AgrC/receptor HPK. (7) Binding of consensus sequences by AgrA/regulatory module. (8) Binding of target mRNAs by RNAIII/fsr/VR-RNA and post-transcriptional regulation of gene expression.
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