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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2021
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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. |
format | Online Article Text |
id | pubmed-8056388 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
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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