Engineering bacterial traps to understand and inspire next-generation antibiotics

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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.