Discovery of ClpP Protein, a Major Regulator in Nitric Oxide Stressed Escherichia coli, for Anti-infective Development Strategies
Princeton Docket # 15-3064
Antibiotic resistance has become a public health crisis, while the rate of new antibiotic development declines. A promising solution is antivirulence therapy, which targets
host-pathogen interactions, rather than vital cellular processes. Because nitric oxide is an important antimicrobial used by the immune system to disable pathogens, and the virulence of many pathogens depends on nitric oxide defense systems, the identification of strategies to impair bacterial nitric oxide defenses may facilitate the development of antivirulence therapies to target essential host-pathogen interactions.
Researchers in the Department of Chemical and Biological Engineering at Princeton University have discovered that the ClpP protein and its specificity factors ClpA and ClpX are critical for E. coli to induce nitric oxide defense systems. Without these proteins, the ability of E. coli to detoxify nitric oxide, an antimicrobial of the immune response, is severely compromised. The underlying mechanism and how perturbation of the ClpP protein increases nitric oxide toxicity in E. coli have been identified. Pathogenic E. coli and other bacterial pathogens require nitric oxide defense systems to establish or sustain infections. Therefore, inhibition of ClpP activity could constitute an anti-infective strategy. Because loss of ClpP activity does not inhibit E. coli growth in the absence of nitric oxide, an inhibitor would produce very little to no selective pressure away from an infection site and outside a host, and it would produce far less damage to commensal flora than conventional antibiotics.
· Anti-infective strategy
· Develop ClpP inhibitors to find effective therapeutic for infection
· Target essential host-pathogen interaction
· Study association with nitric oxide stress and toxicity
· Reduced resistance development
· Less damage to commensal flora than conventional antibiotics
· Expanded range of bacterial species whose nitric oxide defenses depend on ClpP protein than pathogenic E. coli
Nitric oxide, kinetic modeling, Escherichia coli, ClpP protein, anti-infective, antibiotic, cell toxicity, host-pathogen interaction, cell defense system
Robinson, J.L. and Brynildsen M.P. An ensemble-guided approach identifies ClpP as a major regulator of transcript levels in nitric oxide-stressed Escherichia coli. Submitted, 2015.
Robinson J.L. and Brynildsen M.P. A kinetic platform to determine the fate of nitric oxide in Escherichia coli. PLoS Computational Biology, 2013. 9(5):e1003049.
Jonathan Robinson and Mark Brynildsen, Ph.D.
Mark Brynildsen, Assistant Professor in Chemical and Biological Engineering
The Brynildsen research group is a network biology and metabolic engineering lab that uses both computational and experimental techniques in systems biology, synthetic biology, and metabolic engineering to understand and address threats to human health. The lab currently focuses on the global public health crisis of antibiotic resistance and is interested in the specific areas of antivirulence therapy, bacterial persistence, and biofilms.
Dr. Mark Brynildsen completed his graduate work with Professor James Liao in 2008 at the University of California, Los Angeles, where he was awarded the California NanoSystems Institute Graduate Student Fellowship, the Arco Graduate Student Fellowship, and the UCLA Dissertation Year Fellowship. He was an Howard Hughes Medical Institute Postdoctoral Associate at Boston University from 2008-2010. He then joined the faculty of Princeton University in the Department of Chemical and Biological Engineering, where he has started his research group.
Intellectual Property Status
Patent applications are pending. Princeton is seeking industrial collaborators for further development and commercialization of this technology.
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