Description:
A New Target for Pseudomonas aeruginosa Drug Discovery
Princeton Docket # 21-3767
Researchers in the Department of Molecular Biology, Princeton University have developed a novel method to quantify a physical interaction between the proteins called RhlR and PqsE from Pseudomonas aeruginosa, a globally important pathogen. The data show that RhlR-PqsE interaction is required for the bacterium to be virulent. Thus, targeting such proteins or their interaction could be leads for antimicrobial drug development. Additionally it would also be possible to use this method to report on the interaction between the two proteins to screen for compounds that bind and disrupt the interaction. Again, these molecules could form the basis of novel antimicrobial therapies.
Because PqsE regulates RhlR which, in turn, controls biofilm formation and virulence factor production, disrupting the PqsE-RhlR interaction suppresses these important pathogenicity traits. Thus, identifying agents that function as PqsE-RhlR interaction disrupters could be useful in medical applications (catheters, stents, breathing tubes and as medicines…), aquatic applications, fisheries, and other circumstances where Pseudomonas biofilms and virulence factor production are a commercial or medical problems.
Pseudomonas aeruginosa is an opportunistic human pathogen that can cause fatal infections. There exists an urgent need for new, effective antimicrobial agents to combat P. aeruginosa. Many P. aeruginosa virulence factors are under the control of the quorum-sensing-related protein, PqsE, a metallo--hydrolase enzyme. The role PqsE plays in driving virulence factor production involves interaction with the RhlR quorum-sensing receptor. Disruption of this interaction suppresses virulence factor production, virulence gene expression and biofilm formation. Moreover, PqsE catalytic mutants and mutants impaired for interaction with RhlR demonstrate that it is the PqsE-RhlR interaction, not PqsE-mediated catalysis, that is responsible for promoting virulence factor production in P. aeruginosa. These findings provide a new route for drug discovery efforts targeting PqsE.
Applications
- Drug discovery to identify novel agents that disrupt virulence and biofilm formation in pathogenic bacteria
Advantages
- A new target for drug discovery efforts for Pseudomonas aeruginosa
- Unequivocal verification of protein-protein interaction
- The mechanism is novel so the strategy is less prone to development of resistance compared to traditional antimicrobials
Intellectual Property & Development Status
Patent protection is pending.
Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
Publications
https://pubs.acs.org/action/showCitFormats?doi=10.1021/acschembio.1c00049&ref=pdf
The Inventors
Bonnie Bassler is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the National Academy of Medicine. She is a Howard Hughes Medical Institute Investigator and the Squibb Professor and Chair of the Department of Molecular Biology at Princeton University. Bassler received a B.S. in Biochemistry from the University of California at Davis, and a Ph.D. in Biochemistry from the Johns Hopkins University. She performed postdoctoral work in Genetics at the Agouron Institute, and she joined the Princeton faculty in 1994. Dr. Bassler is the recipient of numerous awards including but not limited to the National Academies’ Richard Lounsbery Award, the Wiley Prize in Biomedical Science, the American Society for Microbiology’s Eli Lilly Investigator Award, the Shaw Prize in Medicine, the Dickson Prize in Medicine, and a MacArthur Foundation Fellowship.
Jon E. Paczkowski is currently a Research Scientist at the Wadsworth Center, New York State Department of Health. Formerly, he was the Jane Coffin Child Postdoctoral Fellow in the Princeton Department of Molecular Biology. He earned his Ph.D. at Cornell University. His research specialty is understanding the mechanism of activation and inhibition of quorum-sensing receptors in bacteria and the development of anti-quorum-sensing therapeutics for antibiotic resistant bacteria.
Isabelle Taylor is a postdoctoral fellow in the Bassler Lab. She is the recipient of an NIH Postdoctoral Fellowship. She received her undergraduate degree in Chemistry from Bard College and her PhD degree in Chemical-Biology from the University of California, San Francisco. Her expertise is in small molecule drug development.
Contact:
Laurie Tzodikov
Princeton University Office of Technology Licensing
(609) 258-7256 • tzodikov@princeton.edu