Antimicrobial resistance (AMR) is a global strategic priority and sits within the UK Government's National Risk Register. In 2019 alone, there were an estimated 4.95 million deaths associated with bacterial AMR. Although global pharmaceutical research and development (R&D) spend continues to increase year on year, research into antimicrobial drug discovery is not currently an attractive commercial investment. This has had two major consequences: an ongoing decline of human capital for R&D in this field, and a decline over the longer term in availability of therapeutically effective antibiotics and other antimicrobial agents. Both training the next generation of leadership in the field and innovative approaches to tackle resistance with new therapeutics are urgently required, we aim to tackle both. BicycleTx has a portfolio of research areas that uses a unique technology platform to deliver high quality bi-cyclic peptides as potential therapeutics. This cross-sectional approach places the company in a rare position to commit some significant activity to search for effective antimicrobials alongside therapeutic areas that are typically more profitable, this is admirable. Warwick researchers have international reputation in their ability to develop new biochemical reagents, assays, structural and mechanistic insight into bacterial cell wall (peptidoglycan) biosynthesis. Recently co-located into a new building with state of the art facilities with additional appointments this team can study the whole biochemical pathway across scale, from models in silico, through atomic resolution to single molecules and single cell resolution. In the past year this opened up new tools, techniques and avenues of investigation. Our mostly commonly used antibiotics target peptidoglycan biosynthesis, many of these are natural products, such as penicillins and the wider family of beta-lactam antibiotics, to which resistance has developed, typically by the acquisition of enzymes that catalyse the destruction of the antibiotic or by mutation altering the target of the antibiotic. New molecules that sidestep such resistance mechanisms are really important for future developments. This academic industry partnership between researchers at the University of Warwick and BicycleTx will build upon an existing five year relationship to strengthen the Uk's life science research environment and address the great healthcare challenge which is AMR. The environment created by this partnership will provide training, enabling tools and technologies already in place from the existing relationship to progress through technology readiness levels TRL 2-4 while providing the freedom to explore new higher risk avenues of investigation that will require new targets and methods to be developed from basic research,TRL1, that may become the basis for future development, including the ability to better target Bicycles to penicillin binding proteins of WHO priority pathogens, including better permeation into difficult to kill gram negative bacteria, and access the bacterial cytoplasm and open up still further targets. We will deliver this in four work packages 1: Extending the mechanistic understanding of existing Bicycle Penicillin Binding Protein inhibitors 2: Identification of new Bicycle inhibitors to additional therapeutic targets involved in bacterial cell wall production & maintaining bacterial viability. Adding these into WP1 3: Computational modelling to design next generation molecules to enable Bicycle delivery into the periplasm and cytoplasm of bacteria and evasion of the potential for mutational resistance 4: Combining outputs from WP2 and WP3 to generate novel prototypical antimicrobial agents. Additionally our existing partnership and wider relationships across the AMR sector will facilitate a streamlined working relationship and expectations of delivery, alongside a unique training environment for the next generation of research leaders.

Each year, millions of people die from bacterial infections and tens of millions suffer from the consequences of these infections. The discovery of the drug penicillin once opened the door to treat these infections. However, over time, bacteria have evolved resistance to these essential drugs, making them ineffective. For example, resistance to penicillins can occur when the bacteria produce an enzyme called beta-lactamase that acts by breaking down the penicillin before it kills the bacteria. The World Health Organisation's Director-General has called antimicrobial resistance a "slow tsunami". Left unchecked, many common medical treatments will become useless and many more people will die from infectious diseases. Research is needed to find new drugs. Already, most species of bacteria exhibit resistance to penicillin. Our vision is to create a new class of inhibitors called "Bicycles" (bicyclic peptides), which act similarly to penicillin but are not vulnerable to beta-lactamases. Bicycles are chemically very different to penicillin and were discovered using proprietary "Phage-display" technology at BicycleTx, a medium sized UK pharmaceutical company. This grant will support an expert researcher, with relevant expertise, from the University of Warwick to work with BicycleTx to improve the activity of these Bicycles. Bacteria are protected from the outside world by surrounding themselves with a cell wall. If we can stop this cell wall being made, the bacteria quickly die. Penicillin binding proteins (PBPs) are a family of specialised proteins used by all bacteria to produce the cell wall. As the name suggests, penicillin can bind to PBPs inhibiting their action, thereby preventing cell wall formation and killing the bacteria. Because PBPs are found in all species of bacteria, drugs like penicillin can be used to treat many different bacterial infections and are therefore extensively used by doctors. Bicycles also inhibit PBPs, but they are very new and before they can be used in a clinical setting, they need further optimisation. Several important questions about how they work need to be answered: - How do they interact with PBPs? - What are the methods that bacteria might use to become resistant to Bicycles? - How do we make sure the Bicycles can break into the bacterial cell in order to have their effect on PBPs? To answer these questions, knowledge about PBPs and a number of different techniques are needed. One of the methods used is X-ray crystallography, which allows scientists to observe the 3D, atomic structures of proteins and Bicycles. These structures can be used to make improved versions of Bicycles which have an even stronger ability to inhibit bacteria. If bacteria are grown in the laboratory in the presence of Bicycles, they will slowly evolve resistance. The Bicycle can then be modified in anticipation of the same evolution happening in a clinical setting. To study how well a Bicycle can enter a bacterial cell, we can use a new test developed by BicycleTx. Different Bicycles will be designed and tested for their ability to penetrate bacterial cells. The University of Warwick and the secondee have expertise highly relevant to these fields of study, knowing how penicillin interacts with PBPs and developing new ways to study this and how new inhibitors such a Bicycles might work. By transferring knowledge to BicycleTx, we can accelerate the development of Bicycles. This project addresses the global demand for effective new antibiotics to combat the rising threat of antimicrobial resistance. A new class of antibiotics would help safeguard healthcare systems. The project also boosts the exchange of knowledge between universities and UK pharmaceutical enterprises which will help the UK become a world leader in this field. Finally, the project will boost the career of a young scientist, providing them with the skills, knowledge and professional network for a career in antibiotic innovation.

For the last half-century doctors have routinely used radioactive drugs - radiopharmaceuticals - to detect and diagnose disease in patients and to treat cancer. This speciality is known as nuclear medicine. Modern imaging with radiopharmaceuticals is known as molecular imaging, and treating cancer with them is known as radionuclide therapy. Currently there are economic and geographical barriers, both in the UK and overseas, for patients accessing these scans and treatments. Our programme will develop technologies to perform both molecular imaging and radionuclide therapy more cost-effectively, benefitting more patients and greatly enhancing quality of information, depth of understanding of the disease, and therapeutic benefit. We will use new chemistry to make synthesis of the radiopharmaceuticals faster, more cost-effective and usable in more locations, and hence more accessible for patients. It will improve healthcare by producing and clinically translating new radioactive probes for positron emission tomography (PET), single photon emission computed tomography (SPECT) and radionuclide therapy, to harness the potential of emerging new scanners and therapeutic radionuclides, and provide a diagnostic foundation for emerging advanced therapies. Advanced medicines such as cell-based and immune therapies, targeted drug delivery and radionuclide therapy pose new imaging challenges such as personalised profiling to optimise benefit to patients and minimise risk, and tracking the fate of drug/radionuclide carriers and therapeutic cells in the body. New alpha-emitting radionuclides for cancer therapy are impressing in early trials. New understanding of cancer heterogeneity shows that imaging a single molecular process in a tumour cannot predict treatment outcome. New generation scanners such as combined PET-MR are finding clinical utility, creating niche applications for combined modality tracers; new gamma camera designs and world-wide investment in production of technetium-99m, the staple raw material for gamma camera imaging, demand a new generation of technetium-99m tracers; and "total body PET" will emerge soon, enhancing the potential of long-lived radionuclides for cell and nanomedicine tracking. Demand for new tracers is thus greater than ever, but their short half-life (minutes/hours) means that many of them must be synthesised at the time and place of use. Except for outdated technetium-99m probes, current on-site syntheses are complex and costly, limiting availability, patient access and market size, particularly for modern biomolecule-based probes. Therefore, to grasp opportunities to improve healthcare afforded by the aforementioned advances in therapies and scanners, they must be matched by new chemistry for tracer synthesis. This Programme will dramatically enhance patient access to molecular imaging and radionuclide therapy in both developed and low/middle-income countries, by developing and biologically evaluating faster, simpler, more efficient, kit-based biomolecule labelling with radioactive isotopes for imaging and therapy, streamlining production and reducing need for costly and complex automated synthesisers. In addition, it will maximise future impacts of total body PET, SPECT, PET-MR by evaluating and developing the potential of multiplexed PET to harness the full potential of total body PET: combined imaging of multiple molecular targets, not just one, using fast chemistry for several very short half-live tracers in tandem in a single session to offer a new level of personalised medicine. The programme will also enable the tracking of nanomedicines and cells within the body using long half-life radionuclides - an area where total body PET and PET-MR will be transformative). Finally, we will secure additional funding of selected probes into clinical use in heart disease, cancer, inflammation and neurodegenerative disease.