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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
- Source :
- ACS Chemical Biology. 16:740-752
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
chemistry.chemical_classification
010405 organic chemistry
Chemistry
Pseudomonas aeruginosa
Drug discovery
Tryptophan
Human pathogen
General Medicine
medicine.disease_cause
01 natural sciences
Biochemistry
Virulence factor
0104 chemical sciences
Microbiology
03 medical and health sciences
Quorum sensing
030104 developmental biology
Enzyme
medicine
Molecular Medicine
Receptor
Subjects
Details
- ISSN :
- 15548937 and 15548929
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Biology
- Accession number :
- edsair.doi...........adb192282074294cf6f86a5cbed653f7