N-Methyl and peptoid scans of an autoinducing peptide reveal new structural features required for inhibition and activation of AgrC quorum sensing receptors in Staphylococcus aureus

Tal‐Gan, Yftah; Stacy, Danielle M.; Blackwell, Helen E.

doi:10.1039/c4cc00117f

Cited by 31 publications

(44 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We note, however, that while AIP-II 9aa only inhibited Group-I, AIP-II 9aa was also a highly active agonist for Group-II. These selectively profiles are significant, as few agr group selective probes have been reported in any staphylococcal species (60), and none have been reported in S. epidermidis . Accordingly, these peptides represent a valuable new suite of chemical probes, and hold promise for examining the role of agr -based QS competition between any two agr- groups of S. epidermidis grown together.…”

Section: Resultsmentioning

confidence: 99%

Structure–Function Analyses of a Staphylococcus epidermidis Autoinducing Peptide Reveals Motifs Critical for AgrC-type Receptor Modulation

et al. 2016

Self Cite

View full text Add to dashboard Cite

Staphylococcus epidermidis is frequently implicated in human infections associated with indwelling medical devices due to its ubiquity in the skin flora and formation of robust biofilms. The accessory gene regulator (agr) quorum sensing (QS) system plays a prominent role in the establishment of biofilms and infection by this bacterium. Agr activation is mediated by the binding of a peptide signal (or autoinducing peptide, AIP) to its cognate AgrC receptor. Many questions remain about the role of QS in S. epidermidis infections, as well as in mixed-microbial populations on a host, and chemical modulators of its agr system could provide novel insights into this signaling network. The AIP ligand provides an initial scaffold for the development of such probes; however, the structure-activity relationships (SARs) for activation of S. epidermidis AgrC receptors by AIPs are largely unknown. Herein, we report the first SAR analyses of an S. epidermidis AIP by performing systematic alanine and D-amino acid scans of the S. epidermidis AIP-I. Based on these results, we designed and identified potent, pan-group inhibitors of the AgrC receptors in the three S. epidermidis agr groups, as well as a set of AIP-I analogs capable of selective AgrC inhibition in either specific S. epidermidis agr groups or in another common staphylococcal species, S. aureus. In addition, we uncovered a non-native peptide agonist of AgrC-I that can strongly inhibit S. epidermidis biofilm growth. Together, these synthetic analogs represent new and readily accessible probes for investigating the roles of QS in S. epidermidis colonization and infections.

show abstract

Section: Resultsmentioning

confidence: 99%

Structure–Function Analyses of a Staphylococcus epidermidis Autoinducing Peptide Reveals Motifs Critical for AgrC-type Receptor Modulation

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Despite this success, the AIP backbone remains peptidic in nature and hence suffers such drawbacks as high immunogenicity and lack of stability in vivo . In an attempt to address this problem, modification of single residues in AIP-III through the substitution of amino acids with the corresponding peptoid or N-methyl mimics has generated a few global QQs (George et al, 2008; Tal-Gan et al, 2014). Full conversion of an AIP global inhibitor into a peptido-mimetic has, however, yet to be achieved.…”

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

176

201

View full text Add to dashboard Cite

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.

show abstract

“…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. Towards this goal, we recently reported the 3-D solution-phase structures of the four native AIP signals (I–IV) in S. aureus and several synthetic AIP-III analogues as determined using NMR spectroscopy.…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

N-Methyl and peptoid scans of an autoinducing peptide reveal new structural features required for inhibition and activation of AgrC quorum sensing receptors in Staphylococcus aureus

Cited by 31 publications

References 18 publications

Structure–Function Analyses of a Staphylococcus epidermidis Autoinducing Peptide Reveals Motifs Critical for AgrC-type Receptor Modulation

Structure–Function Analyses of a Staphylococcus epidermidis Autoinducing Peptide Reveals Motifs Critical for AgrC-type Receptor Modulation

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

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

Contact Info

Product

Resources

About