Princeton Docket # 16-3239-1
Researchers in the Department of Molecular Biology at Princeton University have developed an innovative therapy for the treatment of bacterial infections.
The invention combines two unique discoveries to generate a novel, safe approach to combat bacterial infections without generating resistance. The first discovery is small molecule inhibitors of the key quorum sensing (“QS”) regulators in the pathogen P. aeruginosa. QS is required for P. aeruginosa virulence and biofilm formation. The second discovery is that CRISPR-Cas mediated bacterial immunity is activated by QS in P. aeruginosa. Disabling CRISPR-mediated immunity using QS-inhibitors sensitizes P. aeruginosa to bacteriophage (phage) based therapy. Additionally, QS inhibitors prevent P. aeruginosa from expressing virulence traits and from gaining adaptive immunity to administered phage. The invention specifically targets the QS mechanism which regulates biofilm formation, a major mechanism of antibiotic resistance, virulence factor production, and bacterial resistance to phage.
This novel therapeutic use of a QS inhibitor in combination with phage antimicrobial therapy has significant implications for the treatment of infections caused by P. aeruginosa and other ESKAPE pathogens without the development of drug resistance typical of current antibiotic therapies. This antimicrobial combination can also be used in non-clinical antimicrobial products such as hospital disinfectants, water and sewage treatments, animal husbandry, plant pathology, and other applications where phage-based interventions are currently being safely used or are in development. This combination anti-microbial agent has the potential to be generalized to any unwanted bacterium that uses QS to control CRISPR-Cas.
• Therapies for infectious diseases
• Coatings on medical devices
• Hospital disinfectant
• Food decontamination & preservation
• Water safety during disease outbreaks
• Combination therapy is synergistic in anti-microbial action
• The therapy is highly specific, which imposes minimal disturbance to the healthy microbiome
• Minimizes emerging therapeutic resistance
• Potentially effective for treatment of resistant bacteria
Quorum sensing controls the Pseudomonas aeruginosa CRISPR-Cas adaptive immune system. Nina M. Høyland-Kroghsbo , Jon Paczkowski , Sampriti Mukherjee , Jenny Broniewski , Edze Westra , Joseph Bondy-Denomy , and Bonnie L. Bassler. PNAS 2017 Jan 3;114(1):131-135
Jon E. Paczkowskia, Sampriti Mukherjeea, Amelia R. McCreadya, Jian-Ping Conga, Christopher J. Aquinob, Hahn Kimc, Brad R. Henked, Chari D. Smitha, & Bonnie L. Bassler. Flavonoids suppress Pseudomonas aeruginosa virulence through allosteric inhibition of quorum-sensing receptors. J. Biol Chem. 2017 jan 24 M116.770552
Stage of development
We have shown that small molecule QS inhibitors of Pseudomonas aeruginosa suppress CRISPR-Cas expression, activity, and the ability of the system to adapt and acquire new immunity. The QS inhibitors also suppress virulence and biofilm formation.
Bonnie Bassler, Princeton's Squibb Professor and Chair of the Princeton Department of Molecular Biology and a Howard Hughes Medical Institute investigator, is a world leader in the science of quorum sensing. Bassler has won numerous awards, including the 2016 Greengard Prize, 2015 Shaw Prize in Life Science and Medicine, 2012 L’Oreal-UNESCO award for Women in Science, 2011 Richard Lounsbery Award, and 2002 MacArthur Foundation genius award. She has been elected to the National Academy of Science, National Academy of Medicine, Royal Society, American Philosophical Society, and the American Academy of Arts and Sciences, among other honorific organizations.
Jon E. Paczkowski is a 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.
Nina M. Hoeyland-Kroghsbo is a Danish Council for Independent Research Postdoctoral Fellow in the Princeton Department of Molecular Biology. She earned her Ph.D. at the University of Copenhagen, Denmark. Her research addresses how bacteria use quorum sensing to control phage immunity and how to develop targets for therapeutic anti-quorum-sensing therapies. Dr. Hoeyland-Kroghsbo received a 2016 Lundbeck Postdoc Abroad Fellowship to continue her research at the Department of Molecular Biology.
Intellectual Property & Development status
Patent protection is pending.
Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
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