Download CBE-23

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