Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.3.1.184 (
LasR
)
897
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The effects of
2,5-piperazinedione
in reducing the production of quorum sensing (QS)-dependent factors in Pseudomonas aeruginosa PAO1 were assessed both in vitro and in vivo.
2,5-Piperazinedione
exhibited a 69% reduction in the azocasein-degrading proteolytic activity and a 48% reduction in the elastolytic activity of PAO1. Further, it showed 85% and 96% reduction in the production of pyocyanin and extracellular polymeric substances (EPS) of PAO1, respectively. In the swimming inhibition assay,
2,5-piperazinedione
-treated PAO1 cells exhibited poor swimming motility in swim agar medium. In the in vivo analysis, an enhanced survival of PAO1-preinfected Caenorhabditis elegans was observed after treatment with
2,5-piperazinedione
. Regarding the mode of action, in the molecular docking analysis,
2,5-piperazinedione
interacts with the amino acid residue of the
LasR
receptor protein required for binding the natural ligand N -3-oxododecanoyl-l-homoserine lactone (3-oxo-C12-HSL). This demonstrates the probability of
2,5-piperazinedione
to interfere with the binding process of 3-oxo-C12-HSL to its receptor protein. Thus, the findings of the present study reveal the potential of
2,5-piperazinedione
in reducing the QS-dependent phenotypic features of PAO1.
...
PMID:2,5-Piperazinedione inhibits quorum sensing-dependent factor production in Pseudomonas aeruginosa PAO1. 2235 66
Quorum sensing (QS) is a bacterial intercellular communication process which controls the production of major virulence factors, such as proteases, siderophores, and toxins, as well as biofilm formation. Since the inhibition of this pathway reduces bacterial virulence, QS is considered a valuable candidate drug target, particularly for the treatment of opportunistic infections, such as those caused by
Burkholderia cenocepacia
in cystic fibrosis patients.
Diketopiperazine
inhibitors of the
acyl homoserine lactone synthase
CepI have been recently described. These compounds are able to impair the ability of
B. cenocepacia
to produce proteases, siderophores, and to form biofilm, being also active in a
Caenorhabditis elegans
infection model. However, the precise mechanism of action of the compounds, as well as their effect on the cell metabolism, fundamental for candidate drug optimization, are still not completely defined. Here, we performed a proteomic analysis of
B. cenocepacia
cells treated with one of these inhibitors, and compared it with a
cepI
deleted strain. Our results demonstrate that the effects of the compound are similar to the deletion of
cepI
, clearly confirming that these molecules function as inhibitors of the
acyl homoserine lactone synthase
. Moreover, to deepen our knowledge about the binding mechanisms of the compound to CepI, we exploited previously published
in silico
structural insights about this enzyme structure and validated different candidate binding pockets on the enzyme surface using site-directed mutagenesis and biochemical analyses. Our experiments identified a region near the predicted
S
-adenosylmethionine binding site critically involved in interactions with the inhibitor. These results could be useful for future structure-based optimization of these CepI inhibitors.
...
PMID:Investigating the Mechanism of Action of Diketopiperazines Inhibitors of the
Burkholderia cenocepacia
Quorum Sensing Synthase CepI: A Site-Directed Mutagenesis Study. 3010 5
