Norlobaridone Inhibits Quorum Sensing-Dependent Biofilm Formation and Some Virulence Factors in Pseudomonas aeruginosa by Disrupting Its Transcriptional Activator Protein LasR Dimerization

In the present study, norlobaridone (NBD) was isolated from and then evaluated as a new potent quorum sensing (QS) inhibitor against biofilm development. This phenolic natural product was found to reduce biofilm formation (64.6% inhibition) and its related virulence factors, such as pyocyanin and rh...

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Published in:Biomolecules (Basel, Switzerland) Switzerland), 2023-10, Vol.13 (11), p.1573
Main Authors: Soltane, Raya, Alasiri, Ahlam, Taha, Mostafa N, Abd El-Aleam, Rehab H, Alghamdi, Kawthar Saad, Ghareeb, Mosad A, Keshek, Doaa El-Ghareeb, Cardoso, Susana M, Sayed, Ahmed M
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Antibiotics
Bacteria
Bacterial Proteins - metabolism
Biofilms
Dimerization
Enzymes
Infections
Investigations
LasR
Lichens
LuxR-type receptors assay
MD simulation
Natural products
Opportunist infection
Phenolic compounds
Protein structure
Pseudomonas aeruginosa
Pyocyanin
Quaternary structure
Quorum Sensing
thermal shift assay
Trans-Activators - metabolism
Transcription Factors - metabolism
Virulence
Virulence factors
Virulence Factors - metabolism
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Summary:In the present study, norlobaridone (NBD) was isolated from and then evaluated as a new potent quorum sensing (QS) inhibitor against biofilm development. This phenolic natural product was found to reduce biofilm formation (64.6% inhibition) and its related virulence factors, such as pyocyanin and rhamnolipids (% inhibition = 61.1% and 55%, respectively). In vitro assays inhibitory effects against a number of known LuxR-type receptors revealed that NBD was able to specifically block 's LasR in a dose-dependent manner. Further molecular studies (e.g., sedimentation velocity and thermal shift assays) demonstrated that NBD destabilized LasR upon binding and damaged its functional quaternary structure (i.e., the functional dimeric form). The use of modelling and molecular dynamics (MD) simulations also allowed us to further understand its interaction with LasR, and how this can disrupt its dimeric form. Finally, our findings show that NBD is a powerful and specific LasR antagonist that should be widely employed as a chemical probe in QS of , providing new insights into LasR antagonism processes. The new discoveries shed light on the mysterious world of LuxR-type QS in this key opportunistic pathogen.
ISSN:2218-273X
2218-273X
DOI:10.3390/biom13111573