Highly Stable, Amide‐Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in <i>Staphylococcus aureus</i>

Tal‐Gan, Yftah; Ivancic, Monika; Cornilescu, Gabriel; Tian, Yang; Blackwell, Helen E.

doi:10.1002/ange.201602974

Cited by 17 publications

(6 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…25,[29][30][31][32] This strategy has been used in Staphylococcus aureus, a pathogen closely related to S. epidermidis with an analogous agr QS system, and prior studies by our lab and others have revealed several highly potent, non-native antagonists of the agr system in S. aureus. [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Similar to S. aureus, S. epidermidis has evolved into different agr specificity groups (I-III), each with a different AIP signal and some variability in the other components of the agr system (i.e., in proteins AgrB-D). 30,49 Interestingly, these AIP signals are also capable of either inhibiting or activating the receptors of the other S. epidermidis groups, motivating hypotheses about cross-group interactions mediated by QS.…”

Section: Introductionmentioning

confidence: 99%

Conformational Switch to a β-Turn in a Staphylococcal Quorum Sensing Signal Peptide Causes a Dramatic Increase in Potency

et al. 2019

Self Cite

View full text Add to dashboard Cite

We report the solution-phase structures of native signal peptides and related analogs capable of either strongly agonizing or antagonizing the AgrC quorum sensing (QS) receptor in the emerging pathogen Staphylococcus epidermidis. Chronic S. epidermidis infections are often recalcitrant to traditional therapies due to antibiotic resistance and formation of robust biofilms. The accessory gene regulator (agr) QS system plays an important role in biofilm formation in this opportunistic pathogen, and the binding of an autoinducing peptide (AIP) signal to its cognate transmembrane receptor (AgrC) is responsible for controlling agr. Small molecules or peptides capable of modulating this binding event are of significant interest as probes to investigate both the agr system and QS as a potential antivirulence target. We used NMR spectroscopy to characterize the structures of the three native S. epidermidis AIP signals and five non-native analogs with distinct activity profiles in the AgrC-I receptor from S. epidermidis. These studies revealed a suite of structural motifs critical for ligand activity. Interestingly, a unique β-turn was present in the macrocycles of the two most potent AgrC-I modulators-in both an agonist and an antagonistthat was distinct from the macrocycle conformation in the less-potent AgrC-I modulators and in the native AIP-I itself. This previously unknown β-turn provides a structural rationale for these ligands' respective biological activity profiles. Development of analogs to reinforce the β-turn resulted in our first antagonist with subnanomolar potency in AgrC-I, while analogs designed to contain a disrupted β-turn were dramatically less potent relative to their parent compounds. Collectively, these studies provide new insights into the AIP:AgrC interactions crucial for QS activation in S. epidermidis and advance the understanding of QS at the molecular level.

show abstract

Section: Introductionmentioning

confidence: 99%

Conformational Switch to a β-Turn in a Staphylococcal Quorum Sensing Signal Peptide Causes a Dramatic Increase in Potency

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, several attempts to develop inhibitors of the agr system have been pursued using different strategies. Approaches using AIP analogs 48 , identifying natural product inhibitors 49 , and using traditional chemical inhibition 50-55 have yielded promising results. In particular, two compounds, Savirin 54 and ω-Hydroxyemodin (OHM) 55 , are suspected of inhibiting the LytTR domain of AgrA and are likely to behave similarly to the inhibitory compounds reported in the present study.…”

Section: Discussionmentioning

confidence: 99%

Drug-like Fragments Inhibit agr-Mediated Virulence Expression in Staphylococcus aureus

Bezar

Mashruwala

Boyd

et al. 2019

Preprint

View full text Add to dashboard Cite

14In response to the increasingly problematic emergence of antibiotic resistance, novel 15 strategies for combating pathogenic bacteria are being investigated. Targeting the agr 16 quorum sensing system, which regulates expression of virulence in Staphylococcus 17 aureus, is one potentially useful approach for combating drug-resistant pathogens that 18 has not yet been fully explored. A previously published study of a fragment screen 19 resulted in the identification of five compound fragments that interact with the DNA-20 binding domain of the response regulator AgrA from S. aureus. We have analyzed the 21 ability of these compounds to affect agr-mediated virulence gene expression in S. 22 aureus cells. Three of the compounds demonstrated the ability to reduce agr-driven 23 2 transcription of at the P2 and P3 promoters of the agr operon and increase biofilm 24 formation, and two of these compounds also showed the ability to reduce levels of 25 secreted toxins. The finding that the compounds tested were able to reduce agr activity 26 suggests that they could be useful tools for probing the effects of agr inhibition. 27Furthermore, the characteristics of compound fragments make them good starting 28 materials for the development of compound libraries to iteratively improve the inhibitors. 29 30 31 32 Staphylococcus aureus is a dangerous human pathogen and a leading cause of 33 endocarditis, bone and joint infections, pulmonary infections, and bacteremia 1 . S. 34 aureus infections have become increasingly difficult to treat due to the growing 35 prevalence of antibiotic-resistant strains. Methicillin-resistant S. aureus (MRSA) strains 36 such as USA300 have become the predominant source of soft-tissue infections in the 37 USA 2,3 . MRSA infections are often treated with vancomycin as a last-resort antibiotic; 38 however, strains resistant to vancomycin have been reported 4,5 . Although clinical 39 observation of vancomycin resistance in infections has been relatively limited, the threat 40 highlights the urgent need for novel antibiotic therapies 6 . 41 42In response to the problem of increasing antibiotic resistance, targeting bacterial 43 virulence rather than viability has been proposed. Because virulence expression and 44 regulation are important for the establishment and maintenance of an infection but are 45 otherwise non-essential, it has been argued that targeting virulence might be less likely 46 3 to lead to the development of resistance 7,8 . While these potential advantages make the 47 idea of targeting virulence extremely appealing, this strategy remains largely untested. 49In S. aureus, the agr quorum sensing system plays a major role in the regulation of 50 virulence 9 . The agr system coordinates the timing of the transition to an invasive mode 51 that entails increased production of virulence factors and a reduction in surface 52 proteins 10 . Infection models have shown that disruption of the timing of agr activation 53 leads to the attenuation of an infection 11 . The importance of agr-med...

show abstract

“…To address these issues, a new AIP‐III analog containing a non‐native amide bridge, AIP‐III D4A Amide (Figure 6c), was developed, and exhibited improved stability and solubility in aqueous media. [ 75 ]…”

Section: Peptide‐based Qs Systems As Therapeutic Targetsmentioning

confidence: 99%

“…[66,73] Development of non-native synthetic ligands, such as, small peptides and macromolecules capable of inhibition of the AgrC receptor have been promoted by many researchers. [59,71,[73][74][75][76][77] Initial studies have shown that each of the four native staphylococcal AIPs (Table 1) can antagonize the other three, noncognate AgrC receptors to prevent activation of the Agr regulon. [30,71,74,78] Previously, an in vivo study conducted by Wright et al showed that S. aureus pathologies can be reduced by blocking the agr function.…”

Section: Agr Qs System As Therapeutic Targetmentioning

confidence: 99%

“…To address these issues, a new AIP-III analog containing a non-native amide bridge, AIP-III D4A Amide (Figure 6c), was developed, and exhibited improved stability and solubility in aqueous media. [75] As studies suggested that AIP-III might provide a superior scaffold for the development of potent AgrC inhibitors, Blackwell and coworkers further conducted in depth structural analysis of all four native S. aureus AIPs, along with several AIP-III analogs, using 2D NMR (Nuclear Magnetic Resonance) to obtain valuable insight as to the structural features that drive AIP-mediated AgrC activation and inhibition. [73,76,86] The NMR data revealed two important structural motifs within AIP-type ligands that are required for AgrC receptors modulation: (i) the presence of a triangular, hydrophobic knob motif on the macrocycle that is needed for receptor binding, and (ii) a fourth hydrophobic contact or anchor on the N-terminal tail that is essential for receptor activation.…”

Section: Agr Qs System As Therapeutic Targetmentioning

confidence: 99%

See 1 more Smart Citation

Targeting peptide‐based quorum sensing systems for the treatment of gram‐positive bacterial infections

Milly

Tal‐Gan

2022

Peptide Science

Self Cite

View full text Add to dashboard Cite

Bacteria utilize a cell density-dependent communication system called quorum sensing (QS) to coordinate group behaviors. In Gram-positive bacteria, QS involves the production of and response to auto-inducing peptide (AIP) signaling molecules to modulate group phenotypes, including pathogenicity. As such, this bacterial communication system has been identified as a potential therapeutic target against bacterial infections. More specifically, developing synthetic modulators derived from the native peptide signal paves a new way to selectively block the pathogenic behaviors associated with this signaling system. Moreover, rational design and development of potent synthetic peptide modulators allows in depth understanding of the molecular mechanisms that drive QS circuits in diverse bacterial species. Overall, studies aimed at understanding the role of QS in microbial social behavior could result in the accumulation of significant knowledge of microbial interactions, and consequently lead to the development of alternative therapeutic agents to treat bacterial infectivity. In this review, we discuss recent advances in the development of peptide-based modulators to target QS systems in Gram-positive pathogens, with a focus on evaluating the therapeutic potential associated with these bacterial signaling pathways.

show abstract

Highly Stable, Amide‐Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in Staphylococcus aureus

Cited by 17 publications

References 23 publications

Conformational Switch to a β-Turn in a Staphylococcal Quorum Sensing Signal Peptide Causes a Dramatic Increase in Potency

Conformational Switch to a β-Turn in a Staphylococcal Quorum Sensing Signal Peptide Causes a Dramatic Increase in Potency

Drug-like Fragments Inhibit agr-Mediated Virulence Expression in Staphylococcus aureus

Targeting peptide‐based quorum sensing systems for the treatment of gram‐positive bacterial infections

Contact Info

Product

Resources

About