Development of a novel paradigm for local antimicrobial chemotherapy: bacterial protease activated antimicrobial release from hydrogel device coatings

In the UK improved healthcare and a steadily growing population has resulted in an increase in the average male and female life expectancy and a steadily aging UK population. An increase in the population, but especially the elderly or aging population, is set to have major consequences for the NHS. The aging population requires a greater number of medical treatments, hospital admissions and surgical/corrective procedures. In this respect, the use of medical devices (such as catheters) which are inserted into the patients body (to aid or support it's normal functions) are now routinely and frequently used in a variety of clinical settings. Although the use of inserted medical devices has substantial benefits, a worryingly high incidence of potentially serious complications has been reported. In general, complications associated with inserted medical devices lead to an increase in the time spent by patients in hospital, readmissions to hospital and in very serious cases, increase in patient deaths. One of the most common problems arising in the use these devices is the infection associated with the device, where bacteria or fungi grow on the device surface and form a 'protected community' called a biofilm. Once biofilms form on the device it is extremely difficult to treating the infection, once established, without having to remove the device. Depending on the site of the medical device this can be either a simple (urinary tract), if uncomfortable and inconvenient, process or may require serious and life-threatening surgery (i.e. venous catheters or heart prostheses). This aspect of the use of inserted medical devices is the most serious and critical disadvantage to what is otherwise a highly effective, beneficial and often simple medical treatment. Clearly, there is an urgent need to improve the current situation by the development of new and innovative medical devices which actively resist and prevent infection, thereby reducing the incidence of medical device-related infection. The main objective of this research proposal is to improve effectiveness and quality of life for patients who require such medical devices via the development of new, innovative materials which respond to the presence of infecting microorganisms by the release of antibiotic agents. During infection, bacteria use very specific enzymes to break down surrounding tissue proteins and other molecules. This project is aims to harness these very specific protein cutting enzymes, known as proteases, to activate antibiotic release from novel device coatings. In this way antibiotic molecules are released only when the infecting bacteria are present during the development of device-related infection. Antibiotics will accumulate at the device surface at concentrations necessary to kill the infecting bacteria, thus protecting the device, and ultimately the patient, from associated infections. Antibiotic release is thus coordinated with the presence of the infecting microorganisms, such that the device is not permanently releasing drug / a situation difficult to maintain in the long-term and a feature that has been shown to lead to emergence of resistant bacteria such as MRSA. The primary outcome of this project is to improve the highly unsatisfactory situation for patients whose therapy relies on inserted medical device usage by improving the antimicrobial activity and lifetime of these devices. The project will also furnish clear benefits to the NHS by reducing the costs associated with this medical treatment by reducing length hospital stays and readmissions. This will ultimately free funding for numerous other healthcare initiatives and programmes, thus improving overall service provided to patients by the NHS. Furthermore, the benefits of the development of such innovative technologies provide benefits to the medical devices industry by the generation of value-added products, allowing the UK to compete effectively in the world market place.

The most common problem arising from the use of inserted medical devices is the development of infection and biofilm formation at the device surfaces, usually requiring removal of the device. Depending on the site of the medical device this can be either a simple, if uncomfortable and inconvenient, process or may require serious and life-threatening surgery. This aspect of the use of inserted medical devices is the most serious, critical disadvantage to what is an otherwise effective and simple solution. This proposal aims to improve clinical outcomes for patients requiring medical instrumentation via the development of new, innovative materials which respond to the presence of pathogens with the release of antibiotic agents. The strategy proposed details, for the first time, the development of novel drug-polymer conjugates comprising antibiotic molecules modified by the covalent grafting of peptidyl recognition motifs for specific bacterial proteases (protease-activated pro-drug) and a PEGylated spacer group to facilitate presentation of the pro-drug sequence at the hydrogel surface and throughout the matrix. This strategy harnesses the proteolytic activity of soluble proteases produced by bacteria during biofilm formation to activate local release of an antimicrobial from the device coating via cleavage of a peptidyl pro-drug. Co-ordination of release of antimicrobial during bacterial attachment and biofilm formation should prove effective since this approach targets bacteria before biofilm develops and before the nutrient depleted state of a biofilm community results in metabolic quiescence, rendering standard antibiotic therapy ineffective. Antimicrobials will accumulate at the surface at bactericidal concentrations, thus protecting the device and the patient. One advantage of this technology is that antibiotic release is triggered, such that the device is not permanently eluting drug, a feature that is related to emergence of antimicrobial resistance.