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

TitleInhibitor Mimetic Mutations in the PqsE Enzyme Reveal a Protein-Protein Interaction with the Quorum-Sensing Receptor RhlR That Is Vital for Virulence Factor Production.
Publication TypeJournal Article
Year of Publication2021
AuthorsTaylor, IR, Paczkowski, JE, Jeffrey, PD, Henke, BR, Smith, CD, Bassler, BL
JournalACS Chem Biol
Volume16
Issue4
Pagination740-752
Date Published2021 04 16
ISSN1554-8937
KeywordsMolecular Mimicry, Mutation, Pseudomonas aeruginosa, Quorum Sensing, Virulence Factors
Abstract

<p> is an opportunistic human pathogen that causes fatal infections. There exists an urgent need for new antimicrobial agents to combat . 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 . These findings provide a new route for drug discovery efforts targeting PqsE.</p>

DOI10.1021/acschembio.1c00049
Alternate JournalACS Chem Biol
PubMed ID33793200
PubMed Central IDPMC8056388
Grant ListF32 GM134583 / GM / NIGMS NIH HHS / United States
R37 GM065859 / GM / NIGMS NIH HHS / United States