Download 2016 department of medicine research day

2016 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: Identification of Inhibitors of the Francisella Type 6 Secretion System
by High-Throughput Screening
Presenter: Daniel L. Clemens
Division: Division of Infectious Diseases
☒ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☐Other
Principal Investigator/Mentor: Daniel L. Clemens
and Marcus A. Horwitz
Thematic Poster Category:
Atherosclerosis
Co-Investigators: Bai-Yu Lee, Jessica Vo, Robert Damoiseaux,
Infections, Injury and Repair, Inflammation, Host Defense, Immunology, Hemostasis and
Abstract
Francisella tularensis, the bacterial agent of tularemia, is a highly infectious Tier I bioterrorism agent.
Inhalation of as few as 25 F. tularensis bacteria can cause a potentially fatal pneumonic tularemia. F.
tularensis has a type VI secretion system (T6SS), a multi-component membrane-puncturing apparatus
found in 25% of Gram-negative bacteria, that is responsible for bacterial virulence, as it mediates F.
tularensis phagosomal escape and intracellular multiplication in host macrophages. We have identified
conditions that trigger F. tularensis T6SS assembly and secretion and we have developed an EnzymeLinked Immunosorbent (ELISA) based high-throughput screening assay for T6SS secretion. In
addition, we have also developed a split-GFP system that allows us to monitor assembly of the T6SS.
We have used these two assays to screen libraries of small molecules to identify inhibitors of the
Francisella T6SS. Currently there are no antibiotics that target the T6SS. Drugs that target the T6SS
have the potential to treat or prevent tularemia and could also be beneficial for treatment or
prevention of diseases caused by other bacterial pathogens that rely on T6SS for their virulence.
Because the T6SS is critical to the virulence of many pathogens of major clinical significance, including
Vibrio cholerae, Burkholderia mallei, Salmonella enterica sv. typhimurium, Edwardsiella tarda,
Aeromonas hydrophila, enteroaggregative E. coli, and Pseudomonas aeruginosa (which is often
resistant to current antibiotics), the T6SS presents an attractive and novel target for drug
development.