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
posted on 2021-04-01, 23:27authored byIsabelle
R. Taylor, Jon E. Paczkowski, Philip D. Jeffrey, Brad R. Henke, Chari D. Smith, Bonnie L. Bassler
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.