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

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Soltane R.; Alasiri A.; Taha M.N.; Abd El-Aleam R.H.; Alghamdi K.S.; Ghareeb M.A.; Keshek D.E.-G.; Cardoso S.M.; Sayed A.M.

Journal: Biomolecules

Publisher: Multidisciplinary Digital Publishing Institute (MDPI)

Publication Date: 24 October 2023

Volume / Issue: Volume 13 / Issue 11

Article No.: 1573

ISSN: 2218273X

DOI: 10.3390/biom13111573

Scopus: View on Scopus

PubMed: 38002255

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Soltane R., Department of Basic Sciences, Adham University College, Umm Al-Qura University, Makkah, 21955, Saudi Arabia; Alasiri A., Department of Basic Sciences, Adham University College, Umm Al-Qura University, Makkah, 21955, Saudi Arabia; Taha M.N., Microbiology and Immunology Department, Faculty of Pharmacy, Nahda University, Beni-Suef, 62764, Egypt; Abd El-Aleam R.H., Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 11571, Egypt; Alghamdi K.S., Department of Biology, College of Science, University of Hafr Al Batin, Hafar Al Batin, 39511, Saudi Arabia; Ghareeb M.A., Medicinal Chemistry Department, Theodor Bilharz Research Institute Kornaish El Nile, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt; Keshek D.E.-G., Department of Biology, Jumum College University, Umm Al-Qura University, Makkah, 21955, Saudi Arabia, Agriculture Genetic Engineering Research Institute (AGERI), Agriculture Research Center, Giza, 11571, Egypt; Cardoso S.M., LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, 3810-193, Portugal; Sayed A.M., Pharmacognosy Department, Faculty of Pharmacy, Nahda University, Beni-Suef, 62513, Egypt

Abstract

In the present study, norlobaridone (NBD) was isolated from Parmotrema and then evaluated as a new potent quorum sensing (QS) inhibitor against Pseudomonas aeruginosa biofilm development. This phenolic natural product was found to reduce P. aeruginosa 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 P. aeruginosa’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 P. aeruginosa, 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. © 2023 by the authors.

Keywords

LasR; LuxR-type receptors assay; MD simulation; Pseudomonas aeruginosa; quorum sensing; thermal shift assay; Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Dimerization; Trans-Activators; Transcription Factors; Virulence Factors; azithromycin; natural product; norlobaridone; parmotrema tinctorum extract; plant extract; pyocyanine; rhamnolipid; rhamnose; transcription factor; transcriptional activator protein LasR; unclassified drug; virulence factor; antiinfective agent; bacterial protein; transactivator protein; Article; biofilm; carbon nuclear magnetic resonance; colony forming unit; computer model; controlled study; growth curve; minimum inhibitory concentration; molecular docking; molecular dynamics; nonhuman; protein purification; protein structure; proton nuclear magnetic resonance; sedimentation rate; simulation; size exclusion chromatography; chemistry; metabolism

Citation Information

Scopus Citations: 21

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