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Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR.
ACS Chem Biol. 2018 09 21; 13(9):2655-2662.AC

Abstract

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-butanoyll-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 analogues 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.

Authors+Show Affiliations

Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.Department of Chemistry and Biochemistry , Boise State University , 1910 University Drive , Boise , Idaho 83725 , United States.Department of Chemistry and Biochemistry , Boise State University , 1910 University Drive , Boise , Idaho 83725 , United States.Department of Chemistry and Biochemistry , Boise State University , 1910 University Drive , Boise , Idaho 83725 , United States.Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30114353

Citation

Boursier, Michelle E., et al. "Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR." ACS Chemical Biology, vol. 13, no. 9, 2018, pp. 2655-2662.
Boursier ME, Moore JD, Heitman KM, et al. Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR. ACS Chem Biol. 2018;13(9):2655-2662.
Boursier, M. E., Moore, J. D., Heitman, K. M., Shepardson-Fungairino, S. P., Combs, J. B., Koenig, L. C., Shin, D., Brown, E. C., Nagarajan, R., & Blackwell, H. E. (2018). Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR. ACS Chemical Biology, 13(9), 2655-2662. https://doi.org/10.1021/acschembio.8b00577
Boursier ME, et al. Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR. ACS Chem Biol. 2018 09 21;13(9):2655-2662. PubMed PMID: 30114353.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR. AU - Boursier,Michelle E, AU - Moore,Joseph D, AU - Heitman,Katherine M, AU - Shepardson-Fungairino,Sally P, AU - Combs,Joshua B, AU - Koenig,Lea C, AU - Shin,Daniel, AU - Brown,Eric C, AU - Nagarajan,Rajesh, AU - Blackwell,Helen E, Y1 - 2018/08/31/ PY - 2018/8/17/pubmed PY - 2019/4/6/medline PY - 2018/8/17/entrez SP - 2655 EP - 2662 JF - ACS chemical biology JO - ACS Chem. Biol. VL - 13 IS - 9 N2 - 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-butanoyll-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 analogues 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. SN - 1554-8937 UR - https://www.unboundmedicine.com/medline/citation/30114353/Structure_Function_Analyses_of_the_N_Butanoyl_l_Homoserine_Lactone_Quorum_Sensing_Signal_Define_Features_Critical_to_Activity_in_RhlR_ L2 - https://dx.doi.org/10.1021/acschembio.8b00577 DB - PRIME DP - Unbound Medicine ER -