Globally antibiotic treatable infections account for 5.7 million deaths annually where the majority of this mortality burden falls on the populations of least developed low- and middle-income countries (LMICS). This significantly outweighs the 700k deaths, worldwide, currently attributed to antibiotic-resistant infections. However, the increasing threat posed by antimicrobial resistance will further extenuate the disproportionate health burden faced by LMICS. In Africa, deaths attributed to bacterial lower respiratory infections and diarrhoeal diseases together account for nearly 20 percent of all mortality. Strikingly this outnumbers the combined mortality rate of HIV/AIDS, TB and malaria. These headline figures underline the challenge faced by the health care systems in the least developed and lower middle-income countries of Africa. Here, access to frontline antibiotics is hampered by: i) substandard administration and/or unregulated over-the-counter availability, resulting in misuse and overuse; ii) weak supply chains resulting in chronic shortages; and iii) poor quality drugs and falsified medicines from a reliance on imports from generic API drug manufacturers alongside counterfeit drugs. These factors combined lead to unnecessary loss of human life and ever increasing drug resistance. As an example, multiple studies in hospital settings of Klebisella pneumonie isolates (a common urinary tract infection) from Kenya, Tanzania and Nigeria have shown multiple drug resistance (MDR) in 40-75% of cases; worryingly, this number also included samples showing extensive drug resistance. Combined, these studies demonstrate the problem faced across the three partner countries (Kenya, Tanzania, Nigeria), spanning East to West Africa, in accessing effective antibiotic therapies within the constraints of under developed healthcare systems. These nations do not have sustainable access to effective drugs, which we in the UK and the developed world take for granted. This proposal will seek to address this unmet and urgent need partnering with Kenyan, Tanzanian and Nigerian institutes to investigate and apply innovative engineering, novel synthetic biological and chemical solutions toward improving health in Africa, by building capacity in these disciplines and providing sustainable solutions to an efficient and local well-stewarded antibiotic pipeline. This highly integrated project, links experts in industrial synthesis, industrial fermentation, engineering, synthetic biology, drug discovery and medicinal chemistry to build a sustainable antibiotic production pipeline. This will equip our African partners with the capability and capacity not only for equitable production of the most needed antibiotics (categorised by WHO as "access antibiotics") but also addressing our partners' dream for capacity building and training in the discovery of new antibiotics from their own natural resources.

This application builds upon two complementary aspects of our research: -We have previously demonstrated the use of SynBioFilms for enzyme stabilisation, affording long lived, mobilised catalysts with a large surface area -We have demonstrated the discovery and utilisation of a sequence motif for the mining of halogenases with broad substrate specificity. The introduction of a halogen into a molecule can be used to modulate activity, bioavailability and metabolic stability, and as such represents an important strategy in agrochemistry and medicine. Over 20% of small molecule drugs and more than 80% of marketed agrochemicals are halogenated. Furthermore, halogenation is one of the most important reactions for molecule building. In the pharmaceutical industry cross-coupling reactions are widely used (being second only to amide bond forming reactions). Halogenated intermediates are required for cross-coupling reactions. Traditional chemical methodologies of halogenating aromatic substrates generally employ highly reactive reagents and generate harmful waste. As traditional reagents lack components that enable the tuning of product selectivity, they oftentimes generate products in which either only the most nucleophilic position is halogenated or mixtures of products are produced. Conversely, biosynthetic (enzymatic) halogenation is mild, highly selective and utilises simple salts such as NaCl, NH4Br or NaI as the source of halide while oxygen serves as the oxidant. There is an increasing drive to employ greener, and more selective technologies. A global aim is that by 2050 at least 30% of industrial chemical processes will be carried out enzymatically. Halogenase enzymes are notably absent from the industrial catalytic toolbox. Though considerable research has been invested globally into understanding flavin dependent halogenates that halogenate tryptophan, and engineering these halogenates to have slightly broader substrate specificity, there are few studies beyond these simple tryptophan, pyrrole and phenol halogenases. Strikingly, over 5000 halogenated natural products have been found to date. These have notably diverse structures, we therefore had reason to believe halogenases with very different substrate specificities must exist. We have pioneered methodology for the in silico discovery of unique halogenases. Through these studies we have identified for the first time a sequence motif that may be used by itself to mine for enzymes which are definitively halogenases, from sequence data sets. Using this approach Wild Type Halogenases with broad substrate specificity have been found. In this translational project, partnering with experts from the pharmaceutical industry, catalysis industry and a company with expertise in market scoping, and strongly supported by the University of St Andrews who are developing Eden Campus Innovation Hub, underpinned by 26M of City Deal funding we will: - explore the market opportunity, and build upon our relationship with existing partners, whilst proactively identifying and building relationships with new partners and potential customers - carry out proof of concept studies finding bespoke halogenase solutions for our partner company AZ - carry out stabilisation and upscaling of these biotransformations using our engineered SynBioFilm platform - work closely with University of St Andrews, Guy Carter (retired head of Chemical Technologies, Wyeth) and Drochaid (a global catalysis company based in St Andrews) toward spinning out a halogenase solutions company, to be based at the Eden campus Innovation Hub - explore next steps of financing, including licensing deals, partnership deals, investment and the Scottish Enterprise HGSP scheme

The goal of this partnership is to create new catalysts for chemical reactions that are sustainable and help produce important chemicals and intermediates. Catalysts are essential substances that make chemical reactions happen more efficiently, and they are fundamental to many of the key processes that support our modern society. Without effective catalysts, many of the products and processes that we rely on would not be possible. At present, the chemical industry primarily uses fossil carbon sources like natural gas, oil, and coal. However, this approach is not sustainable in the long term, and it contributes to climate change and other environmental problems. As a result, researchers are looking for new ways to make chemicals that rely on green and sustainable carbon sources. Acetylene is one such molecule that has the potential to be an essential intermediate for a sustainable chemical industry. Acetylene chemistry was well developed over a century ago, but it was displaced as a central chemical intermediate by readily available ethene derived from oil. As a result, acetylene chemistry is currently an underexplored field. However, it is possible to produce acetylene from methane, which from biogas is a renewable source of carbon. Therefore, acetylene could become a crucial central intermediate for a new green chemical industry. We aim to design and understand catalysts based on Au, Pt, and AuPt that will act as a new class of catalysts to produce key chemicals and intermediates from acetylene. The partnership will bring together world-leading and complementary catalysis expertise, with the Cardiff Catalysis Institute (CCI collaborating with the UK Catalysis Hub (Harwell), the Max Planck Institute fur Kohlenforschung (KOFO, Mulheim), the Instituto de Tecnologia Quimica (ITQ), and the Fritz-Haber-Institute of the Max Planck Society (FHI, Berlin). A key benefit of this partnership is the additionality that it provides. By pooling expertise and resources, researchers can tackle grand challenge problems more effectively. The collaborative project brings together centres with unique and crucial expertise, such as the high-pressure facilities for acetylene catalysis at MPI KOFO, the fundamental surface science and advanced characterization techniques available at Harwell and FHI, the advanced computational methodologies of the FHI and the synthetic expertise concerning nanoparticles of ITQ. This partnership will enable UK researchers to access this expertise and cutting-edge facilities to tackle the complex challenge of making and characterizing new catalysts. The research will focus on gaining a fundamental understanding of what controls the activity of these catalysts in specific reactions, such as acetylene hydrochlorination and acetylene hydrogenation. Supported Au and Pt catalysts display a range of morphologies and often have individual atoms/cations, clusters, and nanoparticles. In some reactions, it is the well-dispersed Au+ cations that are active, while in others, nanoparticles are active. The research will seek to gain a deeper understanding of what controls the activity in these reactions and use this knowledge to design new and improved catalysts. To achieve these goals, we will use in situ/operando techniques and complementary capabilities available through the partnership to study these new catalysts. The team of experts assembled has worked together previously in various combinations, which will facilitate effective collaboration and communication. The ultimate goal of this partnership is to create new catalysts that will enable the sustainable production of important chemicals and intermediates, contributing to the development of a more sustainable and environmentally friendly chemical industry.

Our CDT in Inorganic Materials for Advanced Manufacturing (IMAT) will provide the knowledge, training and innovation in Inorganic Chemistry and Materials Science needed to power large-scale, high-growth, current and future manufacturing industries. Our cohort-centred programme will build the skills needed to understand, transform and discover better products and materials, and to tackle the practical challenges of manufacturing, application and recycling. IMAT CDT addresses the 'Meeting a user need' CDT focus area, while also addressing 3 EPSRC strategic priorities: 'Physical Sciences Powerhouse', 'Engineering Net Zero' and 'Quantum Technologies'. 'Inorganics' are essential to many industries, from fuel cells to electronics, from batteries to catalysts, from solar cells to medical imaging. These materials are made by technically skilful chemical transformations of elements from across the breadth of the Periodic Table: success is only achievable via in-depth understanding of their properties and dynamic behaviour, requiring systems-thinking across the boundaries of Chemistry and Materials Science. The sector is characterized by an unusually high demand for high-level (MSc/PhD) qualified employees. Moreover, wide-ranging synergies in manufacturing challenges for 'inorganics' mean significant added value is attached to interdisciplinary training in this area. For example, understanding ionic/electronic conductivity is relevant to thermo-electric materials, photo-voltaics, batteries and quantum technologies; replacing heavy metals with earth-abundant alternatives is relevant to chemical manufacturing from plastics to fragrances to speciality chemicals; and methods to manufacture starting from 'natural molecules' like water, oxygen, nitrogen and CO2 will impact nearly every sector of the chemical industry. IMAT will train graduates to navigate interconnected supply chains and meet industry technology/sustainability demands. To invent and propel future industries, graduates must have a clear understanding of scientific fundamentals and be able to quickly apply them to difficult, fast-changing challenges to ensure the UK's leadership in high-tech, high-growth industries. A wide breadth of technical competence is essential, given the sector dominance of small enterprises employing <50 people. The 'inorganic' sector must also meet challenges associated with resource sustainability, manufacturing net zero, pollution minimisation and recycling; our cohorts will be trained to think broadly, with awareness of environmental, societal, legal and economic factors. Our creative and highly skilled graduates will transform sectors as diverse as energy generation, storage, electronics, construction materials, consumer goods, sensing/detection and healthcare. IMAT builds upon the successful EPSRC 'inorganic synthesis' CDT (OxICFM) and (based on extensive end-user/partner feedback) expands its training portfolio to include materials science, physics, engineering and other areas needed to equip graduates to tackle advanced materials challenges. It addresses local, national and international skills gaps identified by our partners, who include companies spanning a wide range of business sizes/sectors, together with local enterprise partnerships and manufacturing catapults. IMAT offers a unique set of training goals in 'inorganic' chemistry and materials - a key discipline encompassing everything made which is not an organic molecule: from salts to composites, from acids/bases to ceramics, from organometallics to (bio)catalysts, from soft-matter to the toughest materials known, and from semi-conductors to super-conductors. A unifying training spanning this breadth is made possible through the strength of expertise across Oxford Chemistry and Materials, and our national partner network. Our goal is to empower future graduates by equipping them with this critical knowledge ready to apply it to new manufacturing sectors.

Many of the small molecules essential to our every-day lives (e.g. pharmaceuticals, clothing, cosmetics, materials, etc.) are currently manufactured from diminishing fossil fuels via industrial processes that contribute significantly to global climate change. Record high atmospheric CO2 levels in 2020 and ambitious net-zero carbon emission targets by 2050 mean that urgent sustainable manufacturing solutions are now required to reduce the environmental burden of this industry on our planet for future generations. The MICROSYN project will uniquely combine cutting-edge modern biological engineering with green chemistry to create transformative solutions to the sustainable manufacture of the nylon-precursor adipic acid from abundant waste generated by the paper-mill industry (lignin) and consumer use (plastic bottles). This will eliminate carbon emissions from the current petrochemical method used to make this compound (currently >20,000,000 ton/year; 5-10% of all human-associated CO2/N2O emissions worldwide) and create circular bioprocesses that avoid the incineration of existing waste streams (releasing further CO2), whilst also addressing the global plastic waste crisis. The project recognizes low-value waste as an underutilized carbon-rich feedstock, and employs modern synthetic biology to transform these abundant and sustainable resources into a high-value chemical via novel biomanufacturing processes.