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Laboratory Learning Program Research Opportunity Research Opportunity Number: CBE-23 Project Title: Metabolic engineering to potentiate immunity and discover novel antivirulence therapies Project Summary: Antibiotic resistance is a growing public health threat that is worsened by a declining antibiotic pipeline. Strains resistant to “last line of defense” antibiotics have appeared and the danger of our antibiotic arsenal becoming obsolete is quite real. Since conventional antibiotic discovery has failed to keep pace with the rise of resistance, novel methodologies are required to address this looming crisis. Antivirulence therapies comprise a novel class of anti-infectives that target host-pathogen interactions required for infection. Since antibiotics exert selective pressure regardless of their location (e.g., inside humans, livestock, sewage, soil) and antivirulence therapies exert selective pressure only at infection sites within the host, antivirulence therapies are projected to be less prone to resistance development than are antibiotics. Further, due to their pathogen-specific nature, they are also predicted to be less harmful to commensal bacteria than are antibiotics. Nitric oxide (NO•) is an antimicrobial generated by immune cells, and its importance to inhibiting pathogenesis is highlighted by the many bacteria that require NO• defense systems to establish or sustain an infection. Disabling pathogen NO• defenses constitutes a promising antivirulence strategy; however, inhibitors of the known elements of these systems are either toxic to humans or suffer from poor transport into bacterial cells. The overall goal of this project is to deepen our quantitative understanding of NO• stress in bacterial pathogens in order to identify novel antivirulence strategies that target NO• defense systems. The challenge of potentiating NO• toxicity in pathogens will be approached as a metabolic engineering problem, which is a paradigm shift from other antivirulence research, and this work will fill fundamental knowledge gaps in understanding of bacterial NO• stress under rarely studied, but physiologically important conditions. Student Roles and Responsibilities: Student is responsible for reading relevant literature, performing experiments with graduate student and/or postdoctoral researcher, keeping a legible laboratory notebook, and participating in group functions, such as weekly meetings. Additional Considerations: Start and end dates are flexible, but the student should be available essentially full-time (at least 35 hours/week) for a minimum of 7 weeks. Department/Institute: Chemical and Biological Engineering Faculty Sponsor: Mark P. Brynildsen Participation Dates: June to August, 2016 Stipend Offered: $0 Number of Internships Available: 0-1 Application Deadline: March 15, 2016, midnight eastern daylight time