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. 2016 Jan 7;14(1):113-21.
doi: 10.1039/c5ob01735a. Epub 2015 Sep 29.

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

Yftah Tal-Gan  1 , Monika Ivancic, Gabriel Cornilescu, Helen E Blackwell
Affiliations

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

Yftah Tal-Gan et al. Org Biomol Chem. .

Abstract

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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Figures

Figure 1
Figure 1
Schematic of the agr QS circuit. The agr locus is comprised of two transcripts termed RNA II and RNA III. The RNA II transcript encodes the four agr components, and the RNA III transcript is the main effector of virulence. AgrD is the precursor of the AIP signal and is processed and exported by AgrB. At high concentrations, the AIP signal binds and activates the transmembrane histidine kinase, AgrC. Activation of AgrC leads to phosphorylation of the response regulator, AgrA, which then binds and activates the P2 and P3 promoters.
Figure 2
Figure 2
A) Heavy atom lowest energy structure of AIP-I D5A. Altered residue labelled in cyan. Space filling models of B) AIP-I and C) AIP-I D5A displaying hydrophobic (yellow) and hydrophilic (green) surfaces. D) Overlay of AIP-I D5A (cyan) and AIP-I (tan) structures. E) Heavy atom lowest energy structure of AIP-I D5N. Altered residue labelled in cyan. F) Space filling model of AIP-I D5N displaying hydrophobic (yellow) and hydrophilic (green) surfaces. G) Overlay of AIP-I D5N (magenta) and AIP-I (tan). H) Overlay of AIP-I D5N (cyan) and AIP-III (tan) structures. AIP-I and AIP-III structures reproduced from ref. .
Figure 3
Figure 3
Heavy atom lowest energy structure for A) tAIP-I; and B) tAIP-I D2A. Altered residue labelled in cyan. C) Overlay of tAIP-I (tan) and tAIP-I D2A (cyan) structures.
Figure 4
Figure 4
A) Heavy atom lowest energy structure of tAIP-II. B) Overlay of AIP-II (tan) and tAIP-II (cyan) structures.
Figure 5
Figure 5
Heavy atom lowest energy structure of: A) S. epidermidis AIP-I; and B) S. lugdunensis AIP-I. Overlay of: C) S. epidermidis AIP-I (tan) and S. lugdunensis AIP-I (cyan) structures; and D) S. epidermidis AIP-I (tan), S. lugdunensis AIP-I (cyan) and tAIPII (magenta) structures.
Figure 6
Figure 6
A) Heavy atom lowest energy structure of AIP-III D4N. Altered residue labelled in cyan. B) Overlay of AIP-III (tan) and AIP-III D4N (cyan) structures.
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