Team:Oxford/Project
PROJECT
Overview
"No action today means no cure tomorrow."
Dr Margaret Chan
WHO Director General, 2011
Antimicrobial resistance is a complex problem driven by many interconnected factors. As such, single, isolated interventions have little impact. Coordinated action is required to minimize emergence and spread of antimicrobial resistance. The aim of our project is to contribute to the growing body of research into providing a solution to the threat of antimicrobial resistance.
The World Health Organisation have recently (May 2015) endorsed a global action plan to tackle antimicrobial resistance.
The plan sets out 5 objectives:
Improve awareness and understanding of antimicrobial resistance
Strengthen surveillance and research
Reduce the incidence of infection
Optimize the use of antimicrobial medicines
Ensure sustainable investment in countering antimicrobial resistance
Our solution considers the first two objectives of this plan: human practices to improve education and awareness of the problem that antibiotic resistance poses and laboratory work to further research into finding alternatives to administering antibiotics. We want to use synthetic biology to provide a solution.
Although bacteria are generally thought of as causing infection, most bacteria that live inside the human body are non-pathogenic and some of them can be turned, after proper engineering, into ‘smart’ living therapeutics that have the potential to treat a diverse range of diseases. We are focused specifically on treating UTIs and, by employing the power of engineered E. coli, we are creating a system that offers persistent protection against biofilm formation in the urinary tract and on the surface of catheters without the use of antibiotics.
What?
The threat of antimicrobial resistance is a serious global public health concern. One of the ways bacteria protect themselves against antimicrobial drugs is by growing biofilms. The biological definition for a biofilm: “an assemblage of surface-associated microorganisms that secrete a mucilaginous protective coating in which they are encased.” Van Leeuwenhoek, using his simple microscopes, first observed microorganisms on tooth surfaces and can be credited with the discovery of microbial biofilms. These bacterial slimes are responsible for a whole host of medical, industrial and environmental problems that are very costly and technically challenging to remedy. Biofilms are involved in catheter and implant infections, dental plaque formation as well as infections in cystic fibrosis patients. Biofilm can be found in the urothelium, prostate stones, and implanted foreign bodies. In industry and infrastructure, biofilms are also the main culprit behind the fouling of various plants and pipelines for aquaculture, water treatment, and food production.
Our solution is focused on providing a treatment for urinary tract infections (UTIs). 90% of urinary infections are caused by uropathogenic E. coli (UPEC) and the biofilm that they form in the urinary tract. Resistance to one of the most widely used antibacterial drugs for the oral treatment of urinary infections caused by E. coli – fluoroquinolones – is now widespread and, with UTIs being the most commonly acquired infection at hospital, there is a huge need to find a solution for the treatment of UTIs and resistance to antimicrobial resistance.
See UTIs facts and figures for more information.
Both antimicrobial resistance and the other problems associated with biofilm formation are big issues in their own right but are especially problematic when they’re combined. The bacteria, already constantly evolving to afford themselves more innate resistance against antibiotics, produce biofilms as protective layers that shield them from the drugs even more comprehensively.
Why?
- UTIs are the most common nosocomial infection
- There is growing resistance to the antibiotics currently used to treat urinary infections
- Biofilms are major problem both in health and industry
- Antibiotics have a negative effect on the beneficial gut flora
- There is a current failure to prevent recurrent infections
"Antimicrobial resistance poses a catastrophic threat. If we don't act now, any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can't be treated with antibiotics."
Professor Dame Sally Davies
Chief Medical Officer, March 2013
How?
There is currently no commercial antibiotic that specifically targets bacterial biofilms, but researchers have identified a range of bacterially-derived biomolecules that degrade and destroy biofilms. Our solution aims to investigate how bacterial biofilm disrupting proteins and antimicrobial proteins can be exported from E. coli.
The proteins DispersinB, MicrocinS, DNase and Endolysin will be fused with secretion tags to target them to normal bacterial secretion pathways. By hijacking the natural processes by which E. coli secrete proteins, we can target our anti-biofilm agents out of E. coli and onto a biofilm infected surface. Additionally, our E. coli will lyse upon sensing the presence of a biofilm, releasing a pulse of proteins from the cytoplasm on detection of a high target cell density.
The beauty of the anti-biofilm agents we plan to use is that they have been shown not to induce resistance in the target bacteria, meaning that having them continually produced at a low level will not be nearly bad as with traditional antibiotics. Our system is applicable to a whole host of biofilm environments and with a simple design that can be used in multiple sectors, we hope to get a step further in providing a novel approach to treating microbial infections. In terms of product formulation and design, we hope to ultimately arrive at a functional proof-of-concept e.g. an enzyme-secreting infection-clearing catheter or a modular system that continuously and cheaply cleans out pipelines.