Bacterial communities often organise in structures called biofilms. These communities are associated with a self-produced matrix containing extracellular DNA, RNA, proteins and complex sugars. Biofilms are resilient to environmental stressors including nutrient fluctuation, antibiotic treatment, and changes in temperature. Biofilm resilience is a valuable strategy to the bacterial collective but presents a colossal economic and health challenge as bacteria in these populations are difficult to eradicate.
The United States National Institutes of health reports that over 80% of microbial infections in the human body are caused by biofilms, many of which are resistant to standard antibiotics. No drug currently in the market specifically targets bacterial biofilms. Chronic human infections are especially serious, as their treatment requires long term antibiotic usage, which can lead to further resistance and require more toxic and last resort antibiotics. Some chronic infections are never fully eradicated, and patients live decades undergoing constant treatment and hospitalisations. All drugs currently in the market target actively dividing bacteria, and therefore are not as efficient eradicating slow growing bacteria, which is often the state encountered in biofilms. Estimates from 2017 indicate an annual global cost of $281bn attributed to biofilms in healthcare wounds.
Extracellular enzymes that can degrade proteins and peptides are important components of biofilms. These proteins are crucial for nutrient scavenging and biofilm remodelling, which is an essential stage of biofilm survival and propagation. They are a very attractive target as antimicrobials do not need to enter cells and can be embedded in dressings and topic gels. The Czekster lab have demonstrated proof of principle that targeting an important extracellular component of the bacterial matrix leads to bacterial cell death in biofilms formed by the pathogenic bacteria Pseudomonas aeruginosa. This work demonstrated the feasibility of exploiting the mechanism by which the activity of extracellular peptidases is regulated to design specific inhibitors, which lead to cell death in a biofilm. It set the stage to the project proposed here.
This project will test two independent hypotheses, firstly on the precise mechanism by which bacteria are dying due to the peptidase inhibition, and secondly on the expansion of our strategy to other extracellular peptidases/proteases to enable therapies targeting multiple extracellular proteins simultaneously. This project is enhanced by collaborations and outstanding facilities and expertise enabling basic biology to inform on inhibitor design and evaluation. It will provide training in several aspects of antibiotic discovery and development. We will employ protein biochemistry, inhibitor design and characterisation, microbial genetics, microbiology, proteomics and metabolomics, in a unique interdisciplinary programme to unveil novel strategies and compounds to specifically target bacterial biofilms.
Project will specifically provide training in enzymatic assays including transient kinetics, protein production and biophysical characterisation using a plethora of techniques (X-ray crystallography, isothermal titration calorimetry, circular dichroism and others), as well as quantitative mass spectrometry (protein and metabolites).
Please direct enquiries to Clarissa Czekster ([Email Address Removed])
How To Apply
Please make a formal application to the School of Biology through our Online Application Portal.
The following documents are required;
- CV
- Personal statement
- Contact details for 2 referees
- Academic qualifications
- English language qualification (if applicable).
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