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Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production

[Image: see text] Pseudomonas aeruginosa is an opportunistic human pathogen that causes fatal infections. There exists an urgent need for new antimicrobial agents to combat P. aeruginosa. We conducted a screen for molecules that bind the virulence-controlling protein PqsE and characterized hit compo...

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Autores principales: Taylor, Isabelle R., Paczkowski, Jon E., Jeffrey, Philip D., Henke, Brad R., Smith, Chari D., Bassler, Bonnie L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056388/
https://www.ncbi.nlm.nih.gov/pubmed/33793200
http://dx.doi.org/10.1021/acschembio.1c00049
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author Taylor, Isabelle R.
Paczkowski, Jon E.
Jeffrey, Philip D.
Henke, Brad R.
Smith, Chari D.
Bassler, Bonnie L.
author_facet Taylor, Isabelle R.
Paczkowski, Jon E.
Jeffrey, Philip D.
Henke, Brad R.
Smith, Chari D.
Bassler, Bonnie L.
author_sort Taylor, Isabelle R.
collection PubMed
description [Image: see text] Pseudomonas aeruginosa is an opportunistic human pathogen that causes fatal infections. There exists an urgent need for new antimicrobial agents to combat P. aeruginosa. We conducted a screen for molecules that bind the virulence-controlling protein PqsE and characterized hit compounds for inhibition of PqsE enzymatic activity. The binding conformations of two inhibitory molecules, BB391 and BB393, were identified by crystallography, and inhibitor binding was mimicked by the substitution of PqsE residues E182 and S285 with tryptophan. Comparison of the inhibitor-mimetic mutations to the catalytically inactive PqsE D73A protein demonstrated that catalysis is not responsible for the role PqsE plays in driving virulence factor production. Rather, the PqsE E182W protein fails to interact with the quorum-sensing receptor, RhlR, and our results suggest that it is this interaction that is responsible for promoting virulence factor production in P. aeruginosa. These findings provide a new route for drug discovery efforts targeting PqsE.
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spelling pubmed-80563882021-04-20 Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production Taylor, Isabelle R. Paczkowski, Jon E. Jeffrey, Philip D. Henke, Brad R. Smith, Chari D. Bassler, Bonnie L. ACS Chem Biol [Image: see text] Pseudomonas aeruginosa is an opportunistic human pathogen that causes fatal infections. There exists an urgent need for new antimicrobial agents to combat P. aeruginosa. We conducted a screen for molecules that bind the virulence-controlling protein PqsE and characterized hit compounds for inhibition of PqsE enzymatic activity. The binding conformations of two inhibitory molecules, BB391 and BB393, were identified by crystallography, and inhibitor binding was mimicked by the substitution of PqsE residues E182 and S285 with tryptophan. Comparison of the inhibitor-mimetic mutations to the catalytically inactive PqsE D73A protein demonstrated that catalysis is not responsible for the role PqsE plays in driving virulence factor production. Rather, the PqsE E182W protein fails to interact with the quorum-sensing receptor, RhlR, and our results suggest that it is this interaction that is responsible for promoting virulence factor production in P. aeruginosa. These findings provide a new route for drug discovery efforts targeting PqsE. American Chemical Society 2021-04-01 2021-04-16 /pmc/articles/PMC8056388/ /pubmed/33793200 http://dx.doi.org/10.1021/acschembio.1c00049 Text en © 2021 The Authors. Published by American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Taylor, Isabelle R.
Paczkowski, Jon E.
Jeffrey, Philip D.
Henke, Brad R.
Smith, Chari D.
Bassler, Bonnie L.
Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production
title Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production
title_full Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production
title_fullStr Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production
title_full_unstemmed Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production
title_short Inhibitor Mimetic Mutations in the Pseudomonas aeruginosa PqsE Enzyme Reveal a Protein–Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production
title_sort inhibitor mimetic mutations in the pseudomonas aeruginosa pqse enzyme reveal a protein–protein interaction with the quorum-sensing receptor rhlr that is vital for virulence factor production
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056388/
https://www.ncbi.nlm.nih.gov/pubmed/33793200
http://dx.doi.org/10.1021/acschembio.1c00049
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