Potent and Selective Modulation of the RhlR Quorum Sensing Receptor by Using Non‐native Ligands: An Emerging Target for Virulence Control in <i>Pseudomonas aeruginosa</i>

Eibergen, Nora R.; Moore, Joseph D.; Mattmann, Margrith E.; Blackwell, Helen E.

doi:10.1002/cbic.201500357

Cited by 53 publications

(74 citation statements)

References 64 publications

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“…We thus assembled a group of small molecules representing some of the most potent synthetic inhibitors of P. aeruginosa QS circuits known. These included: the LasR antagonist 1 , introduced above (Müh et al, 2006, Moore et al, 2015); the RhlR antagonist 2 , reported by our laboratory (Welsh et al, 2015, Eibergen et al, 2015); and the PqsR antagonist 4 , reported by Rahme and coworkers (Figure 1B) (Starkey et al, 2014). Each compound is capable of inhibiting the activity of its target receptor by ≥85% in reporter gene assays (see Figure S2 and the above references for each compound).…”

Section: Resultsmentioning

confidence: 90%

“…Arrows with solid lines indicate direct, positive regulation while arrows with dashed lines indicate positive regulation by indirect or unknown mechanisms. Small molecule QS probes used in this study include the LasR antagonist 1 (V-06-018) (Müh et al, 2006, Moore et al, 2015), the RhlR antagonist 2 (E22) (Welsh et al, 2015, Eibergen et al, 2015), the RhlR agonist 3 (S4) (Welsh et al, 2015), and the PqsR antagonist 4 (M64) (Starkey et al, 2014). …”

Section: Figurementioning

confidence: 99%

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Chemical Genetics Reveals Environment-Specific Roles for Quorum Sensing Circuits in Pseudomonas aeruginosa

Welsh

Blackwell

2016

Cell Chemical Biology

100

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SUMMARY Nutritional cues differentially influence the activities of the three quorum sensing (QS) circuits —Las, Rhl, and Pqs—in the pathogen Pseudomonas aeruginosa. A full understanding of how these systems work together to tune virulence factor production to the environment is lacking. Here, we used chemical probes to evaluate the contribution of each QS circuit to virulence in wild-type P. aeruginosa under defined environmental conditions. Our results indicate that Rhl and Pqs drive virulence factor production in phosphate and iron limiting environments, while Las has a minor influence. Consequently, simultaneous inhibition of Rhl and Pqs can attenuate virulence in environments where Las inhibition fails. The activity trends generated in this study can be extrapolated to predict QS inhibitor activity in infection-relevant environments, such as cystic fibrosis sputum. These results indicate that environmental signals can drastically alter the efficacy of small molecule QS inhibitors in P. aeruginosa and possibly other pathogens.

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Section: Resultsmentioning

confidence: 90%

Section: Figurementioning

confidence: 99%

Chemical Genetics Reveals Environment-Specific Roles for Quorum Sensing Circuits in Pseudomonas aeruginosa

Welsh

Blackwell

2016

Cell Chemical Biology

100

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“…The BHL-derived library can be divided into two groups: ( 1 ) compounds with modified tails and native lactone head groups (i.e., the tail library), and ( 2 ) compounds with modified head groups and native butanoyl tails (i.e., the head library). The tail library compounds can be further divided into three subsets based on structural similarity to either BHL or our two previously reported potent RhlR activators 2 and 3 (28) . The first subset of compounds ( 4 – 11 ) retains the short-chain alkyl characteristics of native ligand BHL, with compounds designed to probe both tail length and alkyl substitution on the tail.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 21 and 22 were previously characterized and included for comparison in the current study (28) .…”

Section: Figurementioning

confidence: 99%

Structure–Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR

et al. 2018

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Pseudomonas aeruginosa is an opportunistic pathogen that coordinates the production of many virulence phenotypes at high population density via quorum sensing (QS). The LuxR-type receptor RhlR plays an important role in the P. aeruginosa QS process, and there is considerable interest in the development of chemical approaches to modulate the activity of this protein. RhlR is activated by a simple, low molecular weight N-acyl L-homoserine lactone signal, N-butanoyl-L-homoserine lactone (BHL). Despite the emerging prominence of RhlR in QS pathways, there has been limited exploration of the chemical features of the BHL scaffold that are critical to its function. In the current study, we sought to systematically delineate the structure-activity relationships (SARs) driving BHL activity for the first time. A focused library of BHL analogs was designed, synthesized, and evaluated in cell-based reporter gene assays for RhlR agonism and antagonism. These investigations allowed us to define a series of SARs for BHL-type ligands and identify structural motifs critical for both activation and inhibition of the RhlR receptor. Notably, we identified agonists that have ~10-fold higher potencies in RhlR relative to BHL, are highly selective for RhlR agonism over LasR, and are active in the P. aeruginosa background. These compounds and the SARs reported herein should pave a route toward new chemical strategies to study RhlR in P. aeruginosa.

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“…This study only failed to reveal ligands that selectively activate AbaR and/or selectively inhibit LasR. Nevertheless, other than some of our past studies, 26–29 the development of ligands with LuxR-type receptor selectivity remains largely unchartered; thus, the discovery of these activity profiles for these ligands in AbaR and LasR is significant. These ligands could be utilized in a range of interesting experiments of both fundamental and direct clinical interest to test the impact of AbaR and LasR modulation in mixed cultures of A. baumannii and P. aeruginosa —mixtures that are relevant to infection populations.…”

Section: Resultsmentioning

confidence: 85%

Chemical Interrogation of LuxR-type Quorum Sensing Receptors Reveals New Insights into Receptor Selectivity and the Potential for Interspecies Bacterial Signaling

et al. 2017

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Cell-cell signaling between bacteria, including quorum-sensing (QS) communication systems, may play a role in the establishment and maintenance of polymicrobial communities. To better understand and model these interactions, we must uncover the degree to which neighboring species recognize each another’s signals. In the current study, we tested the likelihood of whether the QS systems of two opportunistic pathogens (Acinetobacter baumannii and Pseudomonas aeruginosa) that frequently arise in polymicrobial infections would be affected by the QS signals of neighboring species. Through the synthesis and screening of a library of native and non-native N-acyl l-homoserine lactones (AHLs), we found that the AbaR LuxR-type receptor protein of A. baumannii is highly selective for its native AHL signal. However, a homologous LuxR-type receptor in P. aeruginosa, LasR, is far more promiscuously activated by AHLs relative to AbaR, suggesting that LasR-regulated QS could be more susceptible to activation by neighboring species. To explain the observed difference in signal selectivity between AbaR and LasR, we developed a model based on (i) the activity profiles of these proteins and (ii) previously reported structural data and activity profiles for related LuxR-type receptors. This model may facilitate the study of signal selectivities for hundreds of LuxR-type QS receptors from bacteria, many of which grow in polymicrobial communities and may sense each other’s signals. In addition, we discovered a set of AHLs that could be used to selectively activate LasR and selectively inhibit AbaR in polymicrobial experiments.

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Potent and Selective Modulation of the RhlR Quorum Sensing Receptor by Using Non‐native Ligands: An Emerging Target for Virulence Control in Pseudomonas aeruginosa

Cited by 53 publications

References 64 publications

Chemical Genetics Reveals Environment-Specific Roles for Quorum Sensing Circuits in Pseudomonas aeruginosa

Chemical Genetics Reveals Environment-Specific Roles for Quorum Sensing Circuits in Pseudomonas aeruginosa

Structure–Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR

Chemical Interrogation of LuxR-type Quorum Sensing Receptors Reveals New Insights into Receptor Selectivity and the Potential for Interspecies Bacterial Signaling

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