Diphtheria, which re-emerged as a major epidemic disease in Russia andthe Newly Independent States of the former Soviet Union during the 1990s, is a paradigm for toxin-mediated bacterial disease. Tuberculosis, which causes more deaths worldwide than any other bacterial infection, is a paradigm for intracellular bacterial infection. Very similar iron-activated regulatory proteins, called the diphtheria toxin repressor (DbcR) and the iron-dependent regulator (IdeR), control virulence in C. diphtheriae and M. tuberculosis, respectively. Db In Aim 1, using C. diphtheriae, we will characterize the structure and function of several important iron-regulated genes, determine the molecular basis for DtxR-dependent and Db In Aim 2, we will characterize the multiple siderophore-dependent iron-uptake pathways in C. diphtheriae that participate in maintenance of iron homeostasis. We will characterize interaction of diphtheriabactin (the siderophore produced by C. diphtheriae) with its dip0582/ciuA receptor, and we will identify the genetic systems that enable C. diphtheriae to use other siderophores (e.g., desferrioxamine, ferrichrome, rhizoferrin and the recently discovered siderophores from C. pseudotuberculosis).
In Aim 3, we will apply structure- based methods to develop "second-generation" peptides and other molecules with high potency for stimulating or inhibiting Db

Public Health Relevance

Two Closely related iron-dependent regulatory proteins, DtxR and IdeR, control virulence of the bacteria that cause diphtheria and tuberculosis, respectively. Our studies will show how DtxR functions as a master regulator controlling the effects of iron on gene expression and virulence in the diphtheria bacillus. We will use structure-based methods to design novel compounds to activate or inhibit DbcR/ldeR-type regulatory proteins. We will evaluate these compounds for potential value as novel drugs for treatment of tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI014107-37
Application #
8238381
Study Section
Special Emphasis Panel (NSS)
Program Officer
Taylor, Christopher E,
Project Start
1976-09-30
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
37
Fiscal Year
2012
Total Cost
$544,141
Indirect Cost
$188,493
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045