Engineering bacterial traps to understand and inspire next-generation antibiotics

Antimicrobial resistance is rising whereas the development of new antibiotics has stalled: infections that were routinely cured in the past are now becoming life-endangering. This emerging and major health threat calls for radically new ideas and inspiration for next-generation antibiotics. With this project, we aim to provide such new ideas and inspiration based on a deeper understanding of how membrane-targeting antibiotics can kill bacteria and how bacteria can develop resistance against such antibiotics.

Such understanding is still surprisingly scarce, largely due to various technical limitations and due to the complex nature of bacterial cell envelopes. We will overcome some of these limitations and tackle this complexity by making use of our recently developed tools to probe live bacterial surfaces at molecular-scale resolution, using atomic force microscopy (Benn et al., PNAS 2021). To enable such microscopy approaches on live, growing and dividing cells in real time as they are under attack by antibiotics, we will engineer micropatterned surfaces that capture bacteria in suitably functionalised, microfluidic traps within which they are sufficiently immobilised to facilitate nanoscale microscopy, yet not so immobilised that it prevents them from growing and dividing.

Different bacterial strains (sensitive and resistant) will next be imaged at nanometre resolution in such traps as they are exposed to varying doses of antibiotics, and machine-learning based image analyses will used to quantitatively assess bacterial damage throughout the cell cycle and to correlate this with bacterial cell death as measured by fluorescence microscopy.

The 2016 UK Roadmap Bio-design for the Bio-economy highlighted the substantial impact that synthetic biology can bring to the UK and global economies by developing: frontier science and technology; establishing a healthy innovation pipeline; a highly skilled workforce and an environment in which innovative science and businesses can thrive. Synthetic biology promises to transform the UK Bio-economy landscape, bringing bio-sustainable and affordable manufacturing routes to all industrial sectors and will ensure society can tackle many contemporary global Grand Challenges including: Sustainable Manufacturing, Environmental Sustainability Energy, Global Healthcare, and Urban Development. Whilst synthetic biology is burgeoning in the UK, we now need to build on the investments made and take a further lead in training next generation scientists to ensure sustained growth of a capable workforce to underpin the science base development and growth in an advanced UK bio-economy.
This training provided by this CDT will give students from diverse backgrounds a unique synthesis of computational, biomolecular and cellular engineering skills, a peer-to-peer and industrial network, and unique entrepreneurial insight. In so doing, it will address key EPSRC priority areas and Bioeconomy strategic priorities including: Next-generation therapeutics; Engineered biomaterials; Renewable alternatives for fuels, chemicals and other small molecules; Reliable, predictable, and scalable bioprocesses; Sustainable future; Lifelong health & wellbeing.
Advances created by our BioDesign Engineering approach will address major societal challenges by delivering new routes for chemical/pharma/materials manufacture through to sustainable energy, whilst providing clean growth and reductions in energy use, greenhouse gas emissions and carbon footprints. Increased industry awareness of bio-options with better civic understanding will drive end-user demand to create market pull for products. The CDT benefits from unrivalled existing academic-industry frameworks at the host institutions, which will provide direct links to industrial partners and a direct pathway to early economic and industrial impact.

This CDT will develop 80-100 next-generation scientists and technologists (via the funded cohort and wider integration of aligned students at the three institutions) as adept scientists and engineers, instilled with technical leadership, who as broadly trained individuals will fill key skills gaps and could be expected to impact internationally through leadership roles in the medium term. Importantly the CDT addresses key skill-gaps identified with industry, which are urgently required to create and support high value jobs that will enable the UK to compete in global markets. Commercialisation and entrepreneurship training will equip the next generation of visionaries and leaders needed to accelerate and support the creation of new innovative companies to exploit these new technologies and opportunities.

The UK government identified Synthetic Biology as one of the "Eight Great Technologies" that could be a key enabler to economic and societal development. This CDT will be at the forefront of research that will accelerate the clean growth agenda and the development of a resilient circular bioeconomy, and will align with key EPSRC prosperity outcomes including a productive, healthy and resilient nation. To foster wider societal impact, the CDT will expect all students to contribute to public outreach and engagement activities including: open days, schools visits, and science festival events: students will participate in an outreach programme, with special focus on widening participation.

This CDT will contribute to the development of industrial strategy through the Synthetic Biology Leadership Council (SBLC), Industrial Biotechnology Leadership Forum (IBLF), and wider Networks in Industrial Biotechnology and Bioenergy and Professional Institutes.