Corynebacterium diphtheriae is a pathogen in humans and also serves as a model organism for the study of iron-dependent gene regulation in Gram-positive and acid-fast bacterial species. The same mechanisms used by C. diphtheriae to prevent damage caused by oxidative stress in the laboratory will likely be involved in protecting C. diphtheriae from host-defense mechanisms during infection. Aerobic organisms must contain systems to protect themselves from oxidative stress. The goal of this proposal is to examine the mechanisms used by C. diphtheriae to prevent reactive oxygen species from causing damage to cellular components. The role(s) of the diphtheria toxin repressor, DtxR and a probable ferric uptake regulator, Fur, in controlling oxidative stress protection mechanisms will be analyzed. In addition, these experiments will also characterize a new Fur-like transcriptional regulator and determine its role in C. diphtheriae gene expression.
Three specific aims are proposed and a combination of biochemical, genetic and proteomic techniques will be used to accomplish these aims. The three aims of this proposal are : 1) Development of new molecular tools to characterize gene regulation and function in C. diphtheriae, 2) Identification of genes induced by oxidative stress in C. diphtheriae and determine the role of DtxR in their regulation, and 3) Determination of the role of the C. diphtheriae fur-like gene in oxidative stress related transcriptional regulation. The data collected in the experiments described in this proposal will also provide new information on possible mechanisms by which C. diphtheriae evades host defenses. Additionally, the definition of products involved in the oxidative stress response will reveal targets for the development of new antimicrobials. Since DtxR is a model for iron-dependent gene regulation in pathogenic mycobacterial species, the elucidation of its role in oxidative stress response in C. diphtheriae will also lead to insights into mechanisms by which Mycobacterium prevent damage caused by reactive oxygen species. ? ?
| Smith, Kelsy F; Bibb, Lori A; Schmitt, Michael P et al. (2009) Regulation and activity of a zinc uptake regulator, Zur, in Corynebacterium diphtheriae. J Bacteriol 191:1595-603 |
| Oram, Mark; Woolston, Joelle E; Jacobson, Andrew D et al. (2007) Bacteriophage-based vectors for site-specific insertion of DNA in the chromosome of Corynebacteria. Gene 391:53-62 |
