Bacterial and fungal infections are responsible for significant death, disability and poor outcomes and are a major financial burden on the health service. Infections resulting from invasive procedures or injuries whereby the body's own defences are breached are common and are now increasing in incidence and severity due to the rise of antimicrobial resistance. In the past, antibiotics were readily able to treat such infections. This research thus addresses, arguably, the biggest challenge facing modern healthcare, the rise of antimicrobial resistance. The post antibiotic era is looming and novel strategies that do not rely upon conventional antibiotics and antifungals are urgently required. This research proposal will develop to near-clinical readiness, novel classes of therapeutic molecules that will bind specifically to microbes for subsequent activation with low energy light to augment microbial killing. Work on the different elements needed to create this technology platform will be undertaken by investigators at Edinburgh and Liverpool Universities in collaboration with partners in India and in a global surgical network. This project will be based in the Proteus interdisciplinary "hub" to ensure rapid product development. The researchers will spend time in each others labs as well as arranging an open network meeting once a year to ensure broader engagement. The scientists (researcher co-investigators) in the proposal who are all early career researchers will benefit significantly from networking and establishing the area of targeted therapeutic delivery for microbial photodynamic therapy. The research will involve Chemists, Production Engineers, NHS Medical Physics, Bioengineers, industrial collaborators and a committed team of senior clinicians (Respiratory and Critical Care Physicians, Surgeons and Ophthalmologists) to co-develop and test the technology in a variety of model systems to demonstrate the widespread applicability in applications that involve surfaces such as the skin, wounds, eyes and in the lung. A key ambition of the research will be to pave the way for subsequent clinical development and as such user (clinical and regulatory) input will be paramount at the inception and development of the technology. The research will develop and foster global links with an ethos of "safe, affordable and scalable" solutions that will then have the highest likelihood of clinical adoption in a variety of healthcare settings. The team will leverage existing capability and expertise in manufacturing, regulatory and commercialisation support to expedite development. In summary, this project will generate; 1) A cutting-edge point of care technology platform which will help patients, doctors and health care workers throughout the world 2) Career development of the early stage researchers 3) Sustainability for the Proteus IRC by launching into targeted therapy of infection 4) Create a sustainable network to disseminate the technology

The unique properties of light have made it central to our high-tech society. For example, our information-rich world is only enabled by the remarkable capacity of the fibre-optic network, where thin strands of glass are used to carry massive amounts of information around the globe as high-speed optical signals. Light also impacts areas of our society as diverse as laser-based manufacturing, solar energy, space-based remote sensing and even astronomy. One area where the properties of light open up otherwise-impossible capabilities is medicine. In ophthalmology for example, lasers are routinely used to perform surgery on the eye through corneal reshaping. This involves two different lasers. In the first step, a laser producing very short pulses of infrared light cuts a flap in the front surface of the eye to provide access. In the second step, another laser producing longer pulses of ultraviolet (UV) light sculpts the shape of the cornea and correct focusing errors. The flap is then folded back into place so that the cornea can heal. The two very-different laser systems in that example illustrate an important point: the effects of light on human tissues are highly-dependent on the specific properties of both the light and the tissues involved. To sculpt the cornea, the laser wavelength of 193 nm is in the deep UV region of the electromagnetic spectrum, much shorter than the visible range (380 - 740 nm) we are familiar with. This is because (unlike visible light) it is very efficiently absorbed by the cornea, so that essentially all the energy of the light is deposited at the surface. Thus only a very thin layer of tissue (a few microns thick) is removed, or "resected", with each pulse of light, facilitating very-precise shaping of the cornea and accurate adjustment of its focusing properties. 193 nm light can be generated by an ArF excimer gas laser, a >40 year-old technology producing a poor-quality low-brightness beam of light. This is suitable for corneal reshaping, but not for a range of other important therapies requiring higher-quality deep UV beams. Unfortunately, alternative ways to generate such short wavelengths are non-trivial, resulting in complex and expensive laser systems not suitable for widespread clinical uptake. U-care aims to address this gap by exploiting cutting-edge techniques in laser physics. We will develop new sources of deep UV light which will be highly compact, robust and low cost. We will develop ways to deliver this light precisely to tissues, and work to understand in detail the biophysical mechanisms involved. Our efforts will focus on new therapies that target some of the biggest challenges facing medicine: cellular-precision cancer surgery, and the emergence of drug-resistant "super-bugs". Importantly, U-care will involve engineers and physical scientists working in close collaboration with clinicians and biomedical scientists to verify that the therapies we develop are effective and safe. By doing so in an integrated manner, we will drive our deep-UV light therapies towards healthcare impact and widespread use in the clinic by 2050.