Mimetic sugar nucleotides to probe a strategic bacterial dehydrogenase enzyme

This work will use exploratory scientific research to help further understand the way that the infectious bacterium and opportunistic pathogen, P. aeruginosa, regulates its own biosynthetic processes. Infections caused by P. aeruginosa are particularly harmful for sufferers of cystic fibrosis and one critical process that this bacterium utilises here is the production of a protective biofilm, which contributes to the ineffectiveness of standard antibiotic treatments used against it. Bacterial biofilm formation processes are governed by enzymes, which control the formation of key biological building blocks for assembly into the more complex, ultimate biofilm system. It is here that organic chemists can use their expertise to build new molecules to mimic the building blocks used by bacteria, effectively creating a molecular tool to investigate and understand a given enzyme mechanism in more detail. The molecular tools needed to do this are called sugar nucleotides and their construction is an intricate, exciting and diverse activity. Using such tools, important new information about enzyme structure and function can be collected, which could contribute towards instigating new approaches to disrupt specific enzyme activity and potentially arrest normal bacterial biofilm development. It is the purpose of this research to initiate an essential, molecular-level understanding of how a critical enzyme-controlled process operates within this pathogen.

The necessity to successfully treat bacterial infections that can have a debilitating effect on the quality of human life is essential. We as a society rely profoundly upon the advancement of medicine to discover new and effective solutions to address such infections and ensure posterity. Such advances can be aided, in the first instance, by innovative contributions from scientific research within the field of biological chemistry that investigate the basis behind the molecular machinery responsible for bacterial biosynthesis. Ultimately this could instigate a pathway towards new therapeutic targets with the potential to deliver new antibacterial agents. However, before this can happen, synthetic chemists must use their expertise to build molecular tools, capable of probing and trying to understand the mechanisms by which individual pieces of these bacterial biosynthetic machineries operate. This research aims to do just that, through investigating the mechanism of an unexplored, yet pivotal, step in the biosynthesis of the opportunistic pathogen, P. aeruginosa. Beneficiaries of such research within the immediate scientific communities will include: synthetic chemists, enzymologists, bacteriologists, biochemists and structural biologists. Upon delivery of a clearer understanding regarding this process, a broader group of beneficiaries can be envisaged, which could ultimately include the medical and pharmaceutical sectors. The scientific approach described herein will be of significant benefit to the UK chemical biology and biological chemistry footprint, strengthening its presence and international competitiveness within worldwide glycomics research. It will additionally benefit scientific education through increased knowledge and opportunity for the next generation of scientists to evolve their research, based on new understanding.