Bacillus anthracis plasmid-borne gene atxA encodes a major regulator of anthrax toxin expression. Although its role in virulence has been confirmed genetically, the mechanistic details of its action remain obscure. We have discovered that its product, AtxA, binds to anthrax RNA polymerase in vivo, and demonstrated its transcriptional activity in vitro. Using our extensive and in many ways unique experience in elucidating structural and biochemical mechanisms of various bacterial regulators of gene expression we propose a comprehensive plan of AtxA structural and functional research. As a result of the proposed research a detailed understanding of AtxA role in the expression of the anthrax toxin will emerge, complete with in-depth investigation of the molecular mechanism of its action, thorough analysis of the interplay between the differential phosphorylation of this factor and its transcriptional activity, and a high resolution structure of this factor in the "ON" and "OFF" states. Altogether these insights would allow for a better understanding of anthrax virulence and pathogenicity, while serving as a starting point of the structure-based design of AtxA-based inhibitors of anthrax toxin production by this important zoonotic pathogen and a Category A agent.

Public Health Relevance

Bacillis anthracis is a routine cause of zoonotic anthrax infections and has been used as a bioterrorist weapon on the US soil. We propose a comprehensive plan of biochemical and structural research of the main regulator of anthrax virulence and toxin production, transcription factor AtxA. As the result of this research, a detailed understanding of AtxA mechanism of action will emerge while necessary structural and biochemical information will be gathered for its evaluation as a target for knowledge-based drug design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI092010-02
Application #
8204682
Study Section
Special Emphasis Panel (ZRG1-IDM-A (80))
Program Officer
Breen, Joseph J
Project Start
2010-12-15
Project End
2013-02-28
Budget Start
2011-12-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$211,250
Indirect Cost
$86,250
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016