Exploring ribonucleotide reductase as a target to combat bacterial infections


Project leader


Funding source

Swedish Research Council - Vetenskapsrådet (VR)


Project Details

Start date: 01/01/2008
End date: 31/12/2010
Funding: 2850000 SEK


Description

This research proposal will explore ribonucleotide reductase (RNR) as a novel target for highly selective antiproliferative therapies against three severe human pathogens: the opportunistic pathogen Pseudomonas aeruginosa, the anthrax agent Bacillus anthracis, and Mycobacterium tuberculosis the etiological agent of tuberculosis. We will analyze the biological implications for the simultaneous presence of different RNRs in a single microorganism. Due to RNR´s vital importance to provide balanced pools of dNTPs for DNA replication and repair, RNRs are tightly regulated by cell cycle and environmental cues. The regulation is achieved by at least two different regulatory mechanisms, allosteric control of the enzyme and transcriptional regulation of the genes. While a lot of research has been carried out concerning the allosteric regulation of the enzyme, very little is known about the transcriptional mechanisms that regulate the expression of different RNR genes in bacteria. The work plan is divided in three main parts: (i) differential expression studies of RNR genes in each of the three pathogens, (ii) purification and biochemical characterization of the different RNRs, and (iii) screening of chemical libraries to identify potential specific inhibitors of pathogenic RNRs in vitro and in vivo. Results obtained in this study can be extrapolated to other types of pathogenic bacteria containing several RNR classes.

Last updated on 2017-31-03 at 12:58