Inhibiting Quorum Sensing of Bacteria in Healthcare and Industrial Devices Through Conjugation of Anti-Quorum Sensing Molecules to Surfaces

Web Published:
8/7/2017
Description:

A surface-coating approach for bacteria-free health-care and industrial devices 

Docket # 15-3136

 

Bacteria frequently act as members of collectives to create surface-attached communities called biofilms and to synchronously activate the production of virulence factors. Bacterial group behaviors are regulated by a cell-cell communication process called quorum sensing (QS) which involves the production, release, and population-wide detection of extracellular signal molecules called autoinducers. Researchers at Princeton University have invented a process to manipulate QSmediated communication by directly conjugating either anti- or pro-QS compounds to chemically modified surfaces using adaptable and convenient techniques such as click chemistry. The Princeton studies highlight how this surface modification approach can be used to make colonization-resistant materials against Staphylococcus aureus and other pathogens, and how the approach can be adapted to promote beneficial behaviors of bacteria on surfaces.

 

S. aureus is a human pathogen well-known for causing drug-resistant hospital-acquired infections (eg., MRSA) as well as fatal infections outside of health care settings. Current antibiotic treatment strategies exacerbate the problem by inherently selecting for growth of resistant bacteria. By using endogenous bacterial communication molecules to target virulence rather than survival, our technology provides a much greater barrier to resistance than traditional antibiotic drugs. Additionally, in contrast to most antibiotics, autoinducers are highly species-specific, enabling directed targeting of a particular pathogen while protecting beneficial members of the human microbiome. 

 

One prominent avenue for hospital-acquired infections is S. aureus colonization of abiotic medical devices such as intravenous catheters and implants. By covalently tethering QS manipulation molecules to these devices, this technique has site-specificity, generating highconcentration “biofilm-free surfaces” with low systemic exposure and low toxicity risk from the QSmodulating agent. This technique is also broadly applicable, as many species of pathogenic bacteria use QS signaling pathways to control virulent behaviors. Furthermore, the surface-coating chemistry has flexibility and can be used to modify existing devices, create surfaces for new devices, and can also be applied as a direct treatment for patients. The invention has immediate applications for medical and health-care devices in which S. aureus colonization is an urgent unmet need and has potential applications in other devices in which bacterial contamination is a concern. 

 

Advantages: 

•       Targets QS mechanism

•       Much less selective for resistance than traditional antibiotics

•       Can coat any shaped object

•       Can attach to many surfaces including glass, polymer, etc.

 

Applications:        

•       Medical and health-care devices

•       Biofilm formation

•       Filters

•       Orthopedic implants

•       Intubation tubes

•       Water supply lines

 

Stage of Development

We have experimentally verified that conjugation of pro- and anti-QS molecules on glass and polymer surfaces enhance and inhibit, respectively, the colonization of the Gram-positive bacterium S. aureus. We have worked to optimize technical procedures for this species such as QS-molecule density and coated surface shelf life. 

 

Publications

Kim, M. K., Zhao, A., Wang, A., Brown, Z. Z., Muir, T. W., Stone, H. A., & Bassler, B. L. (2017). Surface attached molecules control Staphylococcus aureus quorum sensing and biofilm development. Nature Microbiology, 2, 17080. https://doi.org/10.1038/nmicrobiol.2017.80

 

Bassler, B. L., Stone, H. A., Kim, M. Y., Muir, T. W., & Zhao, A. (2016, November 3). Surfaces comprising attached quorum sensing modulators. Google Patents. Retrieved from https://encrypted.google.com/patents/WO2016176146A1?cl=ru

 

Inventors

 

Min Young Kim was a Ph.D. graduate student in the Department of Chemistry, working with Bonnie L. Bassler (Molecular Biology) and Howard A. Stone (Mechanical Engineering) at Princeton University. He earned his Ph.D. degree at Princeton University in 2017.  He investigated the fundamental mechanisms underlying how bacteria colonize surfaces. He also developed physical and chemical strategies to manipulate bacterial colonization by modulating quorum sensing. Dr. Kim received the STX graduate fellowship in 2012.

 

Aishan Zhao is a graduate student in the Chemistry Department, working with Prof. Tom Muir.  Her research specialty is using chemical biology tools to study the quorum sensing of S. aureus, including biosynthesis of autoinducing peptides, and analysis of signal detection, transduction, and response. She also developed chemical applications for applying quorum sensing signaling molecules to health-care and industrial devices. She received the McKinney Fellowship in 2013.

 

Bonnie L. Bassler, Princeton's Squibb Professor and Chair of the Department of Molecular Biology and a Howard Hughes Medical Institute investigator, is a world leader in the science of quorum sensing and the study of how bacteria communicate. Bassler is a member of the American Academy of Arts and Sciences, National Academy of Sciences, National Academy of Medicine, and the Royal Society. She has won many awards including the 2015 Shaw Prize in Life Sciences and Medicine, the 2011 Richard Lounsbery Award, and the 2002 MacArthur Foundation genius award. 

       

Howard A. Stone is the Donald R. Dixon '69 and Elizabeth W. Dixon Professor and Chair of the Mechanical and Aerospace Engineering Department. In addition to being a member of the American Academy of Arts and Sciences, the National Academy of Engineering, and the National Academy of Sciences, Professor Stone was the winner of the inaugural Batchelor Prize sponsored by the Journal of Fluid Mechanics for the breadth and depth of his research over a 10-year period (1998-2007) and for his widely acknowledged leadership in fluid mechanics generally, as well as the APS Fluid Dynamics Prize in 2016. 

 

Tom W. Muir, Van Zandt Williams, Jr. Class of ’65 Professor of Chemistry and Department Chair. The Muir lab combines tools of synthetic chemistry, protein biochemistry, and cell biology. Prof. Muir received the Irving Sigal Award from the Protein Society, the 2008 Blavatnik Award from the New York Academy of Sciences, and the 2013 Arthur C. Cope Scholar Award from the American Chemical Society. 

 

Intellectual Property Status

Patent protection is pending.

 

Bassler, B. L., Stone, H. A., Kim, M. Y., Muir, T. W., & Zhao, A. (2016, November 3). Surfaces comprising attached quorum sensing modulators. Google Patents. Retrieved from https://encrypted.google.com/patents/WO2016176146A1?cl=ru

 

Industry collaborators are sought to further develop and commercialize this technology. A working prototype for the device is available along with a lead small molecule. 

 

Contacts

Chris Wright

Princeton University Office of Technology Licensing • (609) 258-5579• cw20@princeton.edu

Laurie Tzodikov

Princeton University Office of Technology Licensing • (609) 258-7256• tzodikov@princeton.edu

 

Patent Information:
For Information, Contact:
Laurie Tzodikov
Licensing Associates
Princeton University
tzodikov@Princeton.EDU
Inventors:
Min Kim
Aishan Zhao
Howard Stone
Bonnie Bassler
Tom Muir
Keywords: