Large Scale Production of Antibacterial Peptides by a Synthetic Biology Approach
This research project is in competition for funding with one or more projects available across the EPSRC Doctoral Training Partnership (DTP). Usually the projects which receive the best applicants will be awarded the funding. Find out more information about the DTP and how to apply.
Application deadline: 6 April 2018
Start date: 1 October 2018
Antibiotic resistance has become a global concern and a major threat to public health. Because of overuse, many bacteria have become resistant to most antibiotics including ones that are clinically used as the “last resorts” (e.g. carbapenems). This phenomenon greatly increases the cost of health care and causes 700,000 extra deaths per year.
In fact, if antibiotic resistance is allowed to grow unchecked, infection is anticipated to be the leading cause of hospitalization and mortality in future. To curb the spread of multi-drug resistant pathogens, new and effective antibiotics are urgently needed.
Antibacterial peptides (AMPs) have been viewed as the next generation antibiotics that can be used to eliminate the emergence of drug-resistant pathogens. AMPs and other membrane-disrupting reagents are non-specific among bacteria and thus able to confer inhibitions against a broad range of pathogens.
Although some successful examples that have reached Phase III clinical trials have been seen, several technical issues remained to be solved. These challenges include (a) the relatively high concentrations of AMPs needed to deliver the effect; (b) the low metabolic stability which leads to poor oral bioavailability; and (c) the high cost in producing these peptides.
These challenges need to be immediately addressed in order to fully convert AMPs into clinically used antibiotics.
Project aims and methods
This PhD programme aims to address all the challenges in using AMPs as antibiotics and can be summarised as follows:
- One-pot, multi-step Chemo-Enzymatic Synthesis of Dendrimer-based AMPs (1-24 months): Enzymes offer exquisite site-specificity and -selectivity with superb catalytic efficiency under mild conditions. Here, peptide-engineering enzymes will be used to modify AMPs to increase their chemical stability and subsequently assemble the modified AMPs into a three-dimensional dendrimer. The modified AMPs will have improved oral bioavailability, whereas the dendrimer assembly will generate a high local concentration for effective bacterial inhibition. Because of the one-pot approach, a large amount of AMP dendrimers will be prepared at a relatively low cost.
- Activity examination (25-39 months): The AMP-dendrimers will first be examined in vitro using standard minimal inhibitory concentration (MIC) assays. Successful leads will be further tested with clinically identified antibiotic-resistant pathogens, such as multi-drug resistant Escherichia coli and Klebsiella pneumoniae which are listed as major socioeconomic threats in the most recent O'Niell's Tackling Drug-resistant Infections Global Report.
- Write up (40-42 months): It is anticipated that this work will lead the development of an effective dendrimer-based lead compound. The student will prepare manuscripts and patent whilst finishing his/her thesis.
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