Peptide Signaling in the Staphylococci

Abstract

Gram-negative and Gram-positive bacteria have evolved elaborate machinery to biosynthesize and respond to diverse small-molecule signals. As bacteria grow, these signals accumulate in the extracellular environment until a particular concentration is reached, usually at a specific cell density or “quorum”, activating a regulatory cascade that controls some type of cellular process. This phenomenon is generally referred to as “quorum-sensing” and has been the subject of many excellent review articles1-3. The general paradigm is that Gram-negatives recognize small chemical compounds called N-acyl homoserine lactones that are membrane permeable and bind to a cytoplasmic receptor in order to exert a regulatory output. In contrast, the Gram-positives recognize peptides with diverse post-translational modifications using either a membrane-bound histidine kinase or cytoplasmic receptors. Amongst the Gram-positives, the size and structure of these peptide signals vary widely depending on function and the producing bacterium, and published examples of these regulatory mechanisms have become abundant. As notable examples, Streptococcus pneumoniae regulates competence with a 17-residue linear peptide4. Bacillus subtilis regulates sporulation and competence with a series of linear peptides5, one of which is post-translationally modified6. Bacillus cereus regulates the expression of virulence factors and Enterococcus faecalis controls plasmid-mediated conjugation with various linear peptides7-8. As this quick overview demonstrates, peptides are regulating an impressive array of cellular events, and this list continues to grow as additional systems are being discovered. One of the more intriguing classes of peptide signals are the cyclic lactones and thiolactones. The first of these cyclic peptide signals was discovered in Staphylococcus aureus and is the focus of this review article. The peptide signal controls an autoactivation circuit and hence is referred to as an autoinducing peptide or “AIP”. With the surge of studies on quorum-sensing and bacterial genome sequencing, it is now evident that the AIP scaffold and autoactivation circuitry is conserved among many Gram-positive bacteria9. Notably, all of the staphylococcal species make similar AIP structures10-11, and in recent studies, related signals have been identified in Enterococcus faecalis12-14, Lactobacillus plantarum15-16, Listeria monocytogenes17-18, Clostridium perfringens19-20 and C. botulinum21. Genome mining has revealed additional agr-like systems in other Gram-positives 9, such as the outbreak C. difficile 027 strain22 and in some species of Bacillus. In this review, we will focus on the accessory gene regulator or “agr” quorum-sensing system in S. aureus as a paradigm model. We will describe what is known about the function of each gene product in the agr locus and the mechanism of signal production. Signal sensing and output will be reviewed, along with the contribution of other regulatory inputs to agr function. We will also describe the current status of agr in biofilms and pathogenesis, and outline the latest advances in agr-targeted therapies. Finally, the similarities and differences of the agr system in other Staphylococci will be described.