Highly Potent Inhibitors of Quorum Sensing in Staphylococcus aureus Revealed Through a Systematic Synthetic Study of the Group-III Autoinducing Peptide

Tal‐Gan, Yftah; Stacy, Danielle M.; Foegen, Mary K.; Koenig, David W.; Blackwell, Helen E.

doi:10.1021/ja3112115

Cited by 118 publications

(209 citation statements)

References 72 publications

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“…In that work, repression of TSST-1 was clearly correlated to repression of agr, a well-established positive regulator of TSST-1 expression (10), although the precise details as to how TSST-1 is regulated by agr are not known. Nevertheless, mutation of agr does not completely abolish TSST-1 expression (10,13,15,18), and quorum sensing inhibitors based on the agr autoinducing peptide structure also do not eliminate TSST-1 expression (30). Furthermore, in the agr mutant background, TSST-1 could be further repressed by the lactobacillus signals (18), indicating that repression of TSST-1 was not entirely dependent upon agr.…”

Section: Discussionmentioning

confidence: 99%

The SaeRS Two-Component System Is a Direct and Dominant Transcriptional Activator of Toxic Shock Syndrome Toxin 1 in Staphylococcus aureus

et al. 2016

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Toxic shock syndrome toxin 1 (TSST-1) is a Staphylococcus aureus superantigen that has been implicated in both menstrual and nonmenstrual toxic shock syndrome (TSS). Despite the important role of TSST-1 in severe human disease, a comprehensive understanding of staphylococcal regulatory factors that control TSST-1 expression remains incomplete. The S. aureus exotoxin expression (Sae) operon contains a well-characterized two-component system that regulates a number of important exotoxins in S. aureus, although regulation of TSST-1 by the Sae system has not been investigated. We generated a defined deletion mutant of the Sae histidine kinase sensor (saeS) in the prototypic menstrual TSS strain S. aureus MN8. Mutation of saeS resulted in a complete loss of TSST-1 expression. Using both luciferase reporter experiments and quantitative real-time PCR, we demonstrate that the Sae system is an important transcriptional activator of TSST-1 expression. Recombinant SaeR was able to bind directly to the tst promoter to a region containing two SaeR consensus binding sites. Although the stand-alone SarA transcriptional regulator has been shown to be both a positive and a negative regulator of TSST-1, deletion of sarA in S. aureus MN8 resulted in a dramatic overexpression of TSST-1. As expected, mutation of agr also reduced TSST-1 expression, but this phenotype appeared to be independent of Sae. A double mutation of saeS and sarA resulted in the loss of TSST-1 expression. This work indicates that the Sae system is a dominant and direct transcriptional activator that is required for expression of TSST-1. IMPORTANCEThe TSST-1 superantigen is an exotoxin, produced by some strains of S. aureus, that has a clear role in both menstrual and nonmenstrual TSS. Although the well-characterized agr quorum sensing system is a known positive regulator of TSST-1, the molecular mechanisms that directly control TSST-1 expression are only partially understood. Our studies demonstrate that the Sae two-component regulatory system is a positive transcriptional regulator that binds directly to the TSST-1 promoter, and furthermore, our data suggest that Sae is required for expression of TSST-1. This work highlights how major regulatory circuits can converge to fine-tune exotoxin expression and suggests that the Sae regulatory system may be an important target for antivirulence strategies. Staphylococcus aureus is both a common commensal of humans and a prominent bacterial pathogen that is responsible for an assortment of illnesses ranging from self-limiting superficial infections to life-threatening invasive diseases (1). While most infections caused by S. aureus involve the coordinated expression of numerous virulence factors, a few select diseases, including staphylococcal scalded skin syndrome, food poisoning, and toxic shock syndrome (TSS), require the expression of specific staphylococcal exotoxins (2).Staphylococcal TSS is a rare but devastating disease that is caused by S. aureus strains that secrete high levels of superantigens. Super...

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Section: Discussionmentioning

confidence: 99%

The SaeRS Two-Component System Is a Direct and Dominant Transcriptional Activator of Toxic Shock Syndrome Toxin 1 in Staphylococcus aureus

et al. 2016

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“…23 Following purification of the peptide-Nbz by RP-HPLC, peptide macrocyclization was conducted using our previously reported solution-phase protocol. 9 All cyclic peptides were purified to homogeneity (>98%) by RP-HPLC. Peptide characterization data (MS and HPLC) are provided in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

“…So far, the majority of the SAR studies on AIPs have involved systematic replacement of amino acids with alanine (i.e., alanine scans), 9, 13, 14 D-amino acids (D-AA scans), 9, 14 N -methylated amino acids ( N -methyl scans) 11, 16 or N -alkylated glycine derivatives (peptoid scans). 11, 12 These systematic analyses have provided valuable information regarding the importance of different chemical elements (i.e., side chains, stereochemistry, and hydrogen bonds) to the overall activity of the AIP signals; however, the lack of 3-D structural information for the different AIP analogues has hindered delineation of the structural motifs required for both activation and inhibition of the AgrC receptors.…”

Section: Introductionmentioning

confidence: 99%

Characterization of structural elements in native autoinducing peptides and non-native analogues that permit the differential modulation of AgrC-type quorum sensing receptors in Staphylococcus aureus

et al. 2016

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Staphylococcus aureus uses short macrocyclic peptides (i.e., autoinducing peptides, or AIPs) to assess its local population density in a cell-cell signaling mechanism called quorum sensing (QS). At high cell numbers, this pathogen can initiate many virulent behaviors that allow for the establishment of infection. Binding of the AIP signal to its cognate transmembrane AgrC-type receptor is a critical event in the QS signaling cascade; consequently, interference of AIP:receptor interactions may have the potential to prevent and eradicate certain S. aureus infections. To date, four pairs of AIP:AgrC receptors have been identified in S. aureus, each pair being utilized by a specific S. aureus group (I–IV). Other staphylococcal species also use closely related, but distinct, AIP:AgrC pairs to control QS. We seek to develop non-native ligands capable of intercepting AIP:AgrC binding in each S. aureus group and in related species. As these bacteria may use their respective AIP signal to attenuate the QS systems of other groups/species, such ligands would provide valuable chemical tools to probe possible interference mechanisms in a range of contexts. In the current study, we used solution-phase NMR techniques to characterize the 3-D structures of a set of known native and non-native peptides that have differential modulatory activity in certain AgrC receptors. Analysis of these structures revealed several distinct structural motifs that belay differential activity in selected S. aureus AgrC receptors (i.e., AgrC-I, AgrC-II, and AgrC-III). The results of this study can be leveraged for the design of new synthetic ligands with enhanced selectivities and potencies for these AgrC receptors.

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“…Secondly, hydrophobic residues at the C-terminal end of the peptide, two in AIP-II and three in each of the other AIPs, are necessary (but not sufficient, see below) for tight binding to AgrC (Figure 6A). Alanine point mutations at these positions cause severe loss of potency (Mayville et al, 1999; McDowell et al, 2001; Tal-Gan et al, 2013b). Last, but not least, the agonist activity of an AIP is highly sensitive to structural modification.…”

Section: Reagent Development For the Manipulation Of Agrmentioning

confidence: 99%

Regulation of Virulence in Staphylococcus aureus : Molecular Mechanisms and Remaining Puzzles

Wang

Muir

2016

Cell Chemical Biology

171

201

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Summary The agr locus encodes a quorum sensing (QS) circuit required for the virulence of a spectrum of gram-positive pathogens and is, therefore, regarded as an important target for the development of chemotherapeutics. In recent years, many of the biochemical events in the Staphylococcus aureus agr circuit have been reconstituted and subject to quantitative analysis in vitro. This work, in conjunction with structural studies on several key players in the signaling circuit, has furnished mechanistic insights into the regulation and evolution of the agr quorum sensing system. Herein, we review this progress and discuss the remaining open questions in the area. We also highlight advances in the discovery of small-molecule agr modulators and how the newly available biochemical and structural information might be leveraged for the design of next generation therapeutics targeting the agr system.

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Highly Potent Inhibitors of Quorum Sensing in Staphylococcus aureus Revealed Through a Systematic Synthetic Study of the Group-III Autoinducing Peptide

Cited by 118 publications

References 72 publications

The SaeRS Two-Component System Is a Direct and Dominant Transcriptional Activator of Toxic Shock Syndrome Toxin 1 in Staphylococcus aureus

The SaeRS Two-Component System Is a Direct and Dominant Transcriptional Activator of Toxic Shock Syndrome Toxin 1 in Staphylococcus aureus

Characterization of structural elements in native autoinducing peptides and non-native analogues that permit the differential modulation of AgrC-type quorum sensing receptors in Staphylococcus aureus

Regulation of Virulence in Staphylococcus aureus : Molecular Mechanisms and Remaining Puzzles

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