Non-Native Peptides Capable of Pan-Activating the agr Quorum Sensing System across Multiple Specificity Groups of Staphylococcus epidermidis

Abstract

Staphylococcus epidermidis is a leading cause of hospital-acquired infections. Traditional antibiotics have significantly reduced efficacy against this pathogen due to its ability to form biofilms on abiotic surfaces and drug resistance. The accessory gene regulator (agr) quorum sensing system is directly involved in S. epidermidis pathogenesis. Activation of agr is achieved via binding of the autoinducing peptide (AIP) signal to the extracellular sensor domain of its cognate receptor, AgrC. Divergent evolution has given rise to four agr specificity groups in S. epidermidis defined by the unique AIP sequence used by each group (AIPs-I–IV) with observed cross-group activities. As agr agonism has been shown to reduce biofilm growth in S. epidermidis, the development of pan-group activators of the agr system is of interest as a potential antivirulence strategy. To date, no synthetic compounds have been identified that are capable of appreciably activating the agr system of more than one specificity group of S. epidermidis or, to our knowledge, of any of the other Staphylococci. Here, we report the characterization of the structure–activity relationships for agr agonism by S. epidermidis AIP-II and AIP-III and the application of these new SAR data and those previously reported for AIP-I for the design and synthesis of the first multigroup agr agonists. These non-native peptides were capable of inducing the expression of critical biofilm dispersal agents (i.e., phenol-soluble modulins) in cell culture and represent new tools to study the role of quorum sensing in S. epidermidis infections.

Mechanistic Studies and In Vivo Efficacy of an Oxadiazole-Containing Antibiotic

“…Excitingly, HSGN-94 showed high efficacy in diminishing the burden of MRSA in a murine skin infection model and also reduced the pro-inflammatory cytokines in MRSA-infected wounds. Antimicrobial resistance is a growing threat, and many groups have disclosed new chemical scaffolds that inhibit bacterial growth. − Detailed mechanistic work to uncover how each of these unique compounds kill bacteria would likely reveal many novel tactics to tackle this global health challenge.…”

Peptidomimetics as Potential Anti-Virulence Drugs Against Resistant Bacterial Pathogens

“…Only AIP IV is an agonist on both AgrC I and IV receptors. However, for S. epidermidis , AIP I is an AgrC I activator, but an AgrC II-III antagonist, while AIPs II-III are AgrC II-III activators, but AgrC I antagonists ( West et al, 2021 ). Studies have shown that AIPs’ agonism or antagonism activity could be correlated to twist the linker interdomains (between sensor and HK) of the ArgC receptor ( Wang et al, 2017b ).…”

“…For S. epidermidis , some amino acids in the endocyclic segment (9, 10, 11, and 12) are important for AIP II-III/ArgC interactions, while exocyclic amino acids seem to be efficient for AIP switch activity (agonism/antagonism) ( West et al, 2021 ). For AIP I/ArgC interaction, amino acids positioned at 3, 5, 6, 7, and 8 were seen to be important for AIP I/ArgC interaction, and the third residue was responsible for switch activity ( Yang et al, 2016 ).…”

“…D-enantiomers of AIP III, from S. epidermidis , were tested on AgrC system. Here, the Ser10 epimer held its agonist activity, but when the substitution was on the Lys4 epimer, the peptide showed a strong antagonist activity ( West et al, 2021 ). Other substitutions by D-enantiomers in AIPs II and III reported in this work did not show positive results.…”

Two-Component Systems of S. aureus: Signaling and Sensing Mechanisms

“…Deletion of the tail converts AIP from an agonist into an antagonist molecule [ 118 ]. The structural features of both native AIPs and non-native analogues were revealed using NMR spectroscopy [ 119 , 120 , 121 ]. Two critical structural motifs within the AIP-III ligand were identified: (i) a hydrophobic patch (or “knob”) on the macrocycle essential for receptor binding and (ii) an additional hydrophobic contact or “anchor” on the N-terminal tail critical for receptor activation.…”