Structure-function relation of Ferric uptake regulators and their new inhibitors

Globally, approximately one fourth of all human deaths are caused by bacterial infections. Overuse of antibiotics has induced the development of resistant pathogens, which is an increasing public health problem. The consequence is that new antibacterial c ompounds and new targets must be found Because the link between iron bioavailability and virulence is well established, the Ferric Uptake Regulator (Fur), a global regulator present in most bacteria, could be an interesting antibacterial target. Fur is a transcriptional regulator that uses iron as a cofactor to bind to specific DNA sequences. The main goal of this project is to identify specific inhibitors of Fur proteins from various pathogenic bacteria and to study the structure-function relation in o rder to obtain potential new antibacterial molecules. To fight bacterial infection (by designing novel antibacterial drugs) it is important to gain a basic understanding of the mechanisms used by pathogenic bacteria to overcome the host immune system. I n this study, various computational and experimental methods will be used to achieve a better understanding of the Fur protein from both structural and functional point of views. This project involves a French and a Norwegian group, which have previously collaborated on the mechanistic understanding of activation of Fur regulators for specific DNA interaction after metal binding (Ahmad R, et al. (2009) Proteins). Both groups have expertise that complement each other well. This project should lead t o a better understanding of the mechanisms of inhibition of Fur proteins by peptide inhibitors and give clues to the finding of new generation of specific inhibitors useful for pharmacological purpose as antibacterial agent. The results of this work will be submitted for publication to journals of biochemistry, structural biology and/or microbiology. In addition, it will also be possible to file patents for the novel inhibitors identified from this study.