Triggered bacteriophage release for the treatment of wound infections

Lead Research Organisation: University of Bath
Department Name: Chemistry

Abstract

Wound infections of either accidental wounds or surgical sites arise when microorganisms from the surrounding environment are able to colonise in the wound of a susceptible host. As clinical identification of wound infections can often take time the infection becomes deeper causing conditions such as sepsis & abscess formation. This in turn leads to increased length of hospitalization & hospital costs. Wound infections are a principal mode of hospital-acquired infections (HAI) & remain a significant cause of patient morbidity and mortality. Currently they are treated with systemic antibiotic drugs. However as most pathogenic bacteria are able to form a biofilm, established infections are harder to treat, as bacteria in a biofilm are up to a reported 500 times more resistant to antibiotics. Furthermore the use of broad spectrum &/or prolonged use of antibiotics can predispose patients to colonisation of resistant organisms, eg. MRSA & may contribute to the increasing emergence of antibiotic resistance. Recently the European Wound Management Association has suggested that there is an urgent need to develop antimicrobial treatment regimes that do not include antibiotic drugs. This research aims to detect and treat bacterial wound infections by designing a novel smart wound dressing which releases bacteriophage (bacteria killing viruses) into the wound in response to a trigger event or stimuli, thus giving a burst release of bacteriophage only when required. The research will be split into two parts i) the development & optimisation of bacteriophage cocktails ii) the development of the smart dressing, focusing on treating S. aureus infections, as they are the most commonly isolated pathogen in wounds. Bacteriophage optimisation will involve obtaining & characterising bacteriophages for this study including discovering the bacteriophages spectrum of activity & structure. Next the virulence & spectrum of activity of the chosen bacteriophages will be enhanced using a breeding programme; DNA/RNA characterisation will be undertaken to determine if there are any significant changes & if any genes encoding resistance or virulence factors are present. Finally the phage cocktails will be tested using planktonic bacteria, biofilm models & testing on pigskin. Once the correct phage cocktail has been ascertained it will be incorporated into a wound dressing. Utilising lysin residues it is possible to covalently bind bacteriophage to poly(acrylic acid) PAA hydrogels in the presence of biotin & streptavidin via the formation of ester linkages. Staphylococcus aureus produce esterases as a virulence factor & hence are able to hydrolyse the ester linkage in the PAA hydrogels, releasing the bacteriophage in a burst response, killing the bacteria in the surrounding environment. This project has many benefits over current treatments. The triggered release system utilises bacterial virulence factors produced by the pathogen at the wound site releasing the bacteriophage only in the presence of S. aureus, thereby eliminating non-specific drug release. This could potentially slow down the emergence of resistant bacterial strains. In addition to this using bacteriophage as the antibacterial agent is a viable alternative to antibiotics as they are abundant in nature, easy to isolate, host strain specific, harmless to eukaryotic cells & have had no reports of emerging resistant bacteria. Furthermore this method for detection & treatment of wound infections should be quicker than current treatments, allowing for infections to be treated earlier, reducing the emergence of further issues including sepsis. The main aim of MRC GW4 BioMed DTP Infection, Immunity & Repair theme is to improve human health & focuses on reducing the antimicrobial resistance crisis by looking at viable alternative methods to treat bacterial infections. It is strongly multi-disciplinary, needing both chemistry & microbiology skills to be successful.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
MR/N013794/1 01/10/2016 30/09/2025
1793413 Studentship MR/N013794/1 01/10/2016 31/05/2020 Lauren Gwynne
 
Description President's Fund
Amount £1,200 (GBP)
Organisation Society for Applied Microbiology 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2019 
End 06/2019
 
Description Siegen 
Organisation University of Siegen
Country Germany 
Sector Academic/University 
PI Contribution Myself and my research team have developed numerous enzyme-responsive probes to lead to the detection of bacterial infections in wounds. We have also looked into the role in enzymes and their effectiveness as triggers for stimuli-responsive wound dressings.
Collaborator Contribution Researchers at the University of Siegen have taken our probes to incorporate them in different hydrogel systems to get working sensor strips which can be used in clinical settings.
Impact - One publication under review - Three publications currently being written - Development of novel enzyme-responsive fluorescent probes - Development of novel sensor strips - Leading to development of a theranostic device - Multidisciplinary: Organic chemistry, Physical chemistry, Polymer chemistry, Microbiology
Start Year 2018
 
Description Reddit Q&A 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Reddit users were able to ask questions to my research group for a period of 2 h related to any aspect of our research and we replied with our thoughts/answers to the question. The main outcome of our involvement in this was to broadcast our research, but to also educate and inform the public on bacterial infections, specifically releated to wound or cathether associated infections, to the best of our knowledge. It was also interesting to see what the general public regarded as important, and what kind of questions they wanted answered, as these were very different compared to clinicians/scientists etc. Overall it was a very rewarding experience
Year(s) Of Engagement Activity 2017
URL https://www.reddit.com/r/science/comments/6dgde2/hi_reddit_were_the_biophysical_chemistry_group_at/