The proposed experiments aim to identify novel anti-bacterial drug targets for treatment of chronic wound infections and to carry out screens for small molecule inhibitors of several such targets. To accomplish this goal, we exploit three tools: 1) a newly developed diabetic mouse wound model in which healing is delayed due to a Pseudomonas aeruginosa biofilm infection, 2) a genome-scale genetic approach (Tn- seq) that can identify bacterial functions required for wound infection persistence, and 3) highly sensitive methodology employing mass spectrometry to identify proteins induced in wound infections that may include persistence functions missed by Tn-seq. Potential drug targets will be prioritized using a battery of tests thought to reflect infection. Screening strains designed to detect inhibitors of the three top targets will then be constructed and employed for screening a 200,000 chemical library.

Public Health Relevance

The proposed research seeks to identify therapeutic targets for treatment of chronic Pseudomonas aeruginosa infections of diabetic wounds. The work will employ novel genome-scale technologies to identify and prioritize targets. Inhibitors of several high priority targets will be identified by screening specific reporter strains using a large libray of discrete small molecules and natural products.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI105898-01
Application #
8509966
Study Section
Special Emphasis Panel (ZAI1-JKB-M (J3))
Program Officer
Korpela, Jukka K
Project Start
2013-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$230,115
Indirect Cost
$80,115
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195