Staphylococci are a major burden on our society causing significant morbidity, mortality, and increased cost in healthcare. Increasing this disease burden is their ability to form biofilms on biomaterials resulfing in increased tolerance to anfibiofics and action of the immune system. Further study on the development and maturation of staphylococcal biofilms may lead to novel therapeufics that lead to their disruption. Staphylococcal biofilms are known to display spatial heterogeneity containing several physiological states including aerobic and anaerobic regions. Maintenance of these physiological states is imperative to the development of a mature biofilm. It is hypothesized that arginine catabolism is crucial for the development and maturation of anaerobic regions within both a Staphylococcus aureus and S. epidermidis biofilm. In fact, several backgrounds of both S. aureus and S. epidermidis contain two complete copies of the arginine deiminase (ADI) operon, one of which is acquired on a pathogenicity island. The ADI operon synthesizes proteins which catabolize arginine resulfing in ATP and ammonia. Within certain microniches of a biofllm environment, the resulting ATP can be used for metabolic purposes whereas the ammonia may be used for pH homeostasis. Studies demonstrate that arginine metabolism is induced during biofilm development and that the acquired (i.e. from pathogenicity island) ADI operon is most transcriptionally active as the biofilm matures. The importance of arginine metabolism will be studied by first exploring the regulatory role of ArcR, a known regulator of ADI expression, during biofilm growth. It is hypothesized that maximal inducfion of the acquired ADI operon occurs during biofilm growth and that Induction under these conditions is ArcR- dependent Secondly, through the use of fluorescent gene fusions, we will examine the temporal and spafial pattern of ADI gene expression within a S. epidermidis and S. aureus biofilm and compare those data to known anaerobic and aerobic regions of a biofilm. Lasfiy, through a mouse foreign body infection model, the relative virulence of ADI mutants in comparison to wild type S. aureus and S. epidermidis w' be determined. Suscepfibility of ADI mutants to anfibiotics will be tested in a guinea pig fissue cage model.

Public Health Relevance

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083211-05
Application #
8496678
Study Section
Special Emphasis Panel (ZAI1-TS-M)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$324,793
Indirect Cost
$90,474
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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