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 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.
In Aim 3, we will apply structure- based methods to develop """"""""second-generation"""""""" peptides and other molecules with high potency for stimulating or inhibiting DbPublic Health Relevance
