(309a) An Engineering Approach to Discover Novel Antivirulence Strategies

Authors: 
Brynildsen, M. P., Princeton University

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 begun to appear and the danger of our antibiotic arsenal becoming obsolete is quite real. Since current antibiotic discovery has failed to keep pace with the rise of resistance, novel methodologies are required to address this looming crisis. Antivirulence therapies have been receiving increased attention as a novel class of anti-infectives. Rather than targeting essential bacterial functions, as current antibiotics do, antivirulence therapies target essential host-pathogen interactions required for infection such as adhesion, quorum sensing, and susceptibility to immune attack. These therapies are less prone to resistance development than are antibiotics, and have the potential to fill the widening therapeutic gap caused by the rise of multi-drug antibiotic resistance.

Reactive oxygen and nitrogen species (RNS, ROS) are antimicrobials generated by immune cells to kill bacteria. The importance of RNS and ROS to immune function is evidenced by the many pathogens, including Mycobacterium tuberculosis, Neisseria meningitides, Vibrio cholerae, Salmonella enterica, and enterohemorrhagic Escherichia coli (EHEC), that depend on ROS and/or RNS detoxification to establish or sustain an infection. Inhibitors of these defense systems promise to be potent antivirulence therapies; however, known agents are either toxic to humans or poorly transported into bacterial cells.  In this talk, I will discuss how we use methodologies from systems biology and metabolic engineering to quantitatively study RNS and ROS stress in bacteria, as well as how we have used the resulting knowledge to identify novel ways to sabotage the RNS and ROS defense systems bacteria require for infection.